Protein Families

Phage-type RNA polymerases are single-chain enzymes that synthesize RNA from DNA templates. Mitochondrial members combine the conserved polymerase core with lineage-specific targeting and transcription-factor interactions.

TRAF proteins organize receptor-associated signaling assemblies through conserved interaction domains and variable amino-terminal regions. Their roles include recruiting ubiquitin-system components and controlling inflammatory and survival pathways.

Mre11/Rad32 proteins are DNA-end-processing nucleases that cooperate with Rad50-containing complexes in DNA repair. Their conserved nuclease functions are coupled to DNA-end recognition and organism-specific checkpoint and meiotic programs.

Cyclins are regulatory proteins that control cyclin-dependent kinases. Different cyclin groups specify cell-cycle transitions and other transcriptional or regulatory programs through distinct partners and expression patterns.

RasGAP-related proteins accelerate GTP hydrolysis by small GTPases rather than hydrolyzing free GTP as the principal catalyst themselves. Ras versus Rap preference and regulatory localization vary across the group.

FGGY-family carbohydrate kinases contain paired domains that support ATP-dependent phosphorylation of carbohydrate substrates. Members differ in the small molecules they recognize and the metabolic pathways they serve.

Selenophosphate synthetases generate the selenium donor for selenocysteine biosynthesis, catalysing selenophosphate formation from hydrogen selenide and ATP (EC 2.7.9.3). Catalysis runs through a nucleophile at the tip of a glycine-rich loop, and that nucleophile is itself selenocysteine in the human catalytic paralog SEPHS2 -- a selenoprotein required to make selenoproteins. Bacterial SelD uses a cysteine at the equivalent position instead, so the family tolerates either chalcogen nucleophile. The human paralog SEPHS1 has substituted that position with threonine. Its selenophosphate-synthase role is contested: UniProt records that "several studies suggest that it does not act as a selenophosphate synthase in vivo", and its current recommended name is Zincore component SEPHS1, reflecting a characterised role stabilising zinc-finger transcription factors on DNA rather than in selenium metabolism.

This transporter family includes membrane proteins with citrate-transporter-like architecture and diverse solute preferences. Fungal SPX-containing members connect transport with phosphate homeostasis.

Arthropod cuticle proteins contribute to extracellular cuticular structures, with sequence groups associated with different tissues and developmental stages. Rebers-Riddiford chitin-binding signatures characterize the cuticle-protein branch represented by Drosophila Lcp3.

SERINC/Tms proteins are multipass membrane proteins associated with membrane-lipid organization. Mammalian SERINC3 and SERINC5 have experimentally characterized lipid-scrambling and antiviral functions, while other members are less specifically characterized.

Large eukaryotic family built on the M28 zinc-metallopeptidase fold (protease-associated domain + M28 peptidase domain + transferrin-receptor-like dimerisation domain). It spans functionally very different groups that share the fold but not the chemistry: (1) active binuclear-zinc carboxypeptidases - glutamate carboxypeptidase II (FOLH1/GCPII/PSMA, the best-characterized member, a membrane glutamate carboxypeptidase acting on N-acetyl- aspartyl-glutamate and folyl-poly-gamma-glutamates), NAALAD2, and the related ileal aminopeptidase NAALADL1; (2) the plant AMP1/LAMP1/VP8 clade of putative glutamate carboxypeptidases controlling meristem maintenance; (3) transferrin receptors TFRC/TFR2, which lost peptidase activity and repurposed the ectodomain fold for transferrin binding and endocytic iron import; (4) fungal TRE1/TRE2 and VPS70 trafficking-related proteins; and (5) the vertebrate pseudoenzyme NAALADL2, which retains the fold but has a degenerate active site (the GCPII catalytic-glutamate motif SW-DAEE is SW-GGTA in human NAALADL2) and no established molecular function. The family is therefore a showcase for both taxon-aware and activity-aware PAINT curation: catalytic terms are safe only on the clades that kept the catalytic machinery.

JAMM/MPN-family proteins occur in protein-modification and proteostasis complexes. Catalytic members use metal-dependent hydrolysis, but modifier specificity and activity depend on the protein and its complex context.

Choline/ethanolamine phosphotransferases use activated CDP-aminoalcohol donors to synthesize membrane phospholipids. The family contains choline-selective enzymes, ethanolamine-selective enzymes and dual-specificity CEPT enzymes. Donor specificity and the lipid acceptor define the reaction more precisely than the shared membrane phosphotransferase fold.

DTD-family enzymes remove inappropriate amino acids from aminoacyl-tRNAs, providing a trans-editing checkpoint during translation. The characterized DTD mechanism rejects L-chiral amino acids and can also act on glycine-charged tRNAs; tRNA identity helps distinguish productive proofreading from misediting. The historical D-tyrosyl name is narrower than the established substrate class.

This chemokine-receptor family includes receptors with different chemokine specificities and signaling outputs. CXCR3 recognizes C-X-C chemokines, but other branches recognize C-C or XC ligands, and atypical receptors handle chemokines without the same canonical signaling response. Even CXCR3 splice isoforms can differ in their effects on cell migration and proliferation.

SmG/Lsm7-family proteins are small RNA-associated subunits of heptameric ribonucleoprotein rings. SmG participates in the canonical Sm ring of several spliceosomal snRNPs. Lsm7 instead participates in Lsm complexes, including the U6-associated ring and the cytoplasmic mRNA-decapping ring.

UCH-family cysteine proteases hydrolyze bonds at the ubiquitin C terminus. Their conserved catalytic framework serves different biological settings: small-conjugate processing, proteasome-associated deubiquitination and chromatin-associated deubiquitination. Regulatory extensions and partner complexes help determine substrate access.

RP/EB-related proteins use a calponin-homology region to associate with microtubules. Canonical end-binding proteins organize growing microtubule ends and recruit partner proteins, while specialized members can connect stable microtubule bundles to other cellular structures. The fly Mst27D example links nuclear pores to bundled microtubules during sperm nuclear elongation.

Copper amine oxidases oxidatively deaminate primary amines, producing an aldehyde, ammonia and hydrogen peroxide through copper/topaquinone-dependent chemistry. Family members differ in their preferred monoamine, diamine or polyamine substrates and in whether they act intracellularly, at membranes or extracellularly.

HEAT-repeat regulatory scaffolds organize phosphatase complexes. PP2A A subunits assemble catalytic and regulatory partners; the retrieved family also includes PP4 regulatory proteins. Scaffold binding is distinct from catalytic dephosphorylation.

Peptide amidation proceeds through monooxygenase and lyase reactions, carried in separate proteins or combined in bifunctional PAM. Copper/ascorbate-dependent monooxygenase chemistry and PAL lyase chemistry reside in different structural modules.

This group contains bacterial ribosomal S1 proteins alongside S1-domain proteins such as Tex and other RNA-associated proteins. RNA-binding architecture is shared more broadly than incorporation into a ribosomal subunit.

uL4-family proteins are structural components of the large ribosomal subunit. Bacterial and organellar homologues share the ribosome-associated role, but the cellular location and translation system depend on lineage and targeting. Pombe Yml6 belongs to the mitochondrial uL4 group.

Family of mitochondrial carrier homologs (MTCH1, MTCH2 and their metazoan orthologs, including Drosophila Mtch), integral proteins of the mitochondrial outer membrane built on a diverged SLC25 solute-carrier fold. PANTHER keeps this family separate from the canonical metabolite-transporting mitochondrial carrier families, which is biologically correct: no member has demonstrated transport activity, and the family as a whole has been co-opted away from the carrier function. Human MTCH2 (and MTCH1) were established in 2022 as the insertases for alpha-helical mitochondrial outer membrane proteins (signal-anchored, tail-anchored, and multi-pass substrates; not beta-barrels), the metazoan functional analog of the yeast MIM complex despite no sequence homology to Mim1/Mim2. Secondary, likely downstream, roles include acting as an OMM receptor for truncated BID in apoptosis (best characterized for mouse Mtch2 and human MTCH1), and regulation of mitochondrial fusion, lipid homeostasis, and stem-cell state transitions reported in mouse Mtch2 models. Current PAINT curation (July-August 2026 IBDs) asserts the insertase trio (GO:0005741, GO:0032977, GO:0045040) at ancestral node PTN000845785 and positive regulation of apoptosis at PTN001324730; the cached human GOA slice predates those IBDs, so human MTCH2 does not yet show the insertase IBAs and still carries older, more generic IBAs (mitochondrion, membrane) from a prior PAINT iteration that the current snapshot has superseded.

Myotubularins include phosphoinositide phosphatases and inactive partners such as MTMR9 and MTMR12. Inactive homologs can stabilize and regulate active partners while lacking the intrinsic catalytic reaction.

VAP proteins provide membrane-associated docking surfaces for lipid-transfer and other trafficking proteins. Canonical VAPA/VAPB and yeast Scs proteins use an MSP domain to recognize FFAT-containing partners, helping organize membrane contacts rather than transporting lipids through an intrinsic catalytic site.

This dolichol-phosphate glycosyltransferase family contains enzymes producing different lipid-linked sugar donors. ALG5 transfers glucose from UDP-glucose to dolichyl phosphate, whereas DPM-type enzymes generate dolichyl-phosphate mannose. Both feed glycosylation pathways but the sugar donor and product are different.

uS13-related proteins contribute to the structure and function of the small ribosomal subunit. The family includes bacterial-type and mitochondrial uS13 proteins as well as eukaryotic cytosolic counterparts. The mitochondrial small-subunit protein Sws2 therefore shares a ribosomal function without sharing the localization of every family member.

This domain-rich family contains extracellular proteins with distinct inhibitory and signaling roles. Kazal-containing protease inhibitors coexist in the classification with follistatin-related proteins and larger extracellular organizers. A shared cysteine-rich domain does not identify either the inhibited protease or the growth-factor ligand.

FtsJ/RlmE-related methyltransferases modify ribose groups in RNA. The family includes bacterial ribosomal RNA enzymes, mitochondrial Mrm2 and eukaryotic enzymes acting on tRNA or preribosomal RNA. RNA type, modified nucleotide and subcellular location define the important functional boundaries. Human MRM2 also has a ribosome-assembly function that does not require its methyltransferase activity, and disrupting its fly ortholog causes mitochondrial developmental defects.

Eukaryote-wide family of small coiled-coil proteins (about 190-350 residues) typified by Aspergillus nidulans NudE, the first member found, as a multicopy suppressor of the LIS1-homolog mutant nudF. Every characterized member binds LIS1 (NudF/Pac1/LIS-1) through an N-terminal coiled coil and works with it to regulate cytoplasmic dynein. In vitro and in cells, NudE proteins tether LIS1 to dynein, help dynein reach microtubule plus ends, and promote the LIS1-dependent high-force, activated dynein state. The conserved biological output is dynein-driven nuclear migration along microtubules (hyphal nuclear distribution in filamentous fungi, spindle/nuclear positioning in budding yeast, nuclear migration in C. elegans hypodermal and P-cell precursors, nucleokinesis in migrating mammalian neurons) and dynein-driven retrograde organelle and endosome transport. Vertebrates carry two paralogs, NDE1 (SF2) and NDEL1 (SF0), which have gained a C-terminal region that binds CENP-F and other partners. That region targets them to kinetochores, the nuclear envelope and centrosomes in mitosis and neurodevelopment. Kinetochore targeting via CENP-F-like proteins is shared with fly NudE and worm NUD-2, but has not been shown for any fungal member. Centrosome residence and effects on centrosomal microtubule nucleation are documented only for the vertebrate paralogs. The family therefore has one conserved molecular role (the LIS1-dynein regulatory coiled coil) with metazoan and vertebrate additions that the deep PAINT node does not distinguish.

GFAT enzymes couple glutamine hydrolysis to conversion of fructose-6-phosphate into glucosamine-6-phosphate, supplying the hexosamine biosynthetic pathway. Related sugar-isomerase domains also occur in glucosamine deamination and other reactions, so a broad structural grouping extends beyond the complete two-domain GFAT reaction.

HES/HEY-related bHLH proteins regulate developmental transcription through partner-dependent dimerization, DNA recognition and corepressor interactions. Direct zebrafish experiments show that Her7:Hes6 heterodimers bind cyclic-gene promoters strongly whereas Hes6 homodimers do not. Developmental process, DNA-binding competence and repressive output vary among family members and dimer combinations.

Importin/exportin relatives are soluble transport receptors that carry selected proteins through the nuclear pore. Importin-7/Moleskin belongs to an import-receptor branch, while other members of this family include importin-8/9/11 and exportin-2. Cargo recognition and transport direction are central functional distinctions.

This family groups insect CHK/ecdysteroid-kinase-like proteins. The kinase-like architecture raises a specific hypothesis of small-molecule phosphorylation, including ecdysteroid phosphorylation, rather than automatically implying phosphorylation of proteins. Individual members remain unevenly characterized.

SmF/Lsm6 proteins are related small subunits of RNA-associated rings. SmF belongs to canonical spliceosomal Sm particles; Lsm6 is shared by the nuclear U6-associated Lsm2-8 ring and the cytoplasmic Lsm1-7 mRNA-decapping ring. Complex identity therefore changes the biological process assigned to a member.

The peptidoglycan recognition proteins (PGRPs) share the bacteriophage T7 lysozyme amidase-2 fold, which binds bacterial peptidoglycan. The fold is catalytic in its ancestral form: members that retain a zinc site are N-acetylmuramoyl-L-alanine amidases (EC 3.5.1.28) that hydrolyse the lactyl-amide bond linking the glycan backbone to the stem peptide, scavenging immunostimulatory peptidoglycan fragments. A large part of the family has lost the zinc site and repurposed the same binding surface for pattern recognition: these members are receptors that bind peptidoglycan and signal, notably the Drosophila and mosquito PGRP-LC and PGRP-LE receptors that activate the IMD pathway. Catalytic and non-catalytic members therefore share a fold, a ligand, and a name, while differing in whether they turn the ligand over.

NDRG-family proteins are alpha/beta-hydrolase-fold interaction proteins with diverse regulatory roles. Human and mouse NDRG2 structures support a nonenzymatic scaffold rather than a conventional hydrolase; the shared fold does not specify a conserved enzymatic substrate or signaling pathway.

This kinase family combines cell-cycle inhibitory kinases with stress-responsive translation-control kinases and other related enzymes. WEE1-family proteins inhibit CDK-driven mitotic entry, whereas eIF2-alpha kinases control translation during specific stresses. Shared protein-kinase chemistry does not imply common substrates or phosphoacceptor specificity.

Small membrane subunit family of the proton-pumping NADH:quinone oxidoreductases: bacterial NuoA, mitochondrial ND3, and the plastid-encoded NdhC of the chloroplast NDH complex. Bacterial and mitochondrial members are respiratory, reducing ubiquinone in NDH-1 or respiratory complex I. The plastid NdhC clade belongs to the thylakoid NAD(P)H dehydrogenase complex (GO:0010598), which runs photosynthetic cyclic electron flow around photosystem I and chlororespiration and reduces plastoquinone. The compartment-neutral complex term (NADH dehydrogenase complex) is true family-wide; the ubiquinone-specific activity term is not.

Sirtuins couple NAD consumption to removal of acyl groups from protein lysines, with substantial variation in acyl-group preference and cellular substrate selection. SIRT5 is specialized toward negatively charged lysine acylations such as succinylation, malonylation and glutarylation. Nuclear histone regulation and mitochondrial metabolic control are different branch contexts.

Beta adaptins are large subunits of heterotetrameric adaptor complexes that sort membrane cargo. AP-1, AP-2, AP-3 and AP-4 operate at different membrane-trafficking steps and differ in coat partnerships. The beta-adaptin fold identifies a trafficking component without fixing a single organelle or vesicle coat.

Inositol 5-phosphatases remove the phosphate at the 5 position of soluble inositol phosphates or membrane phosphoinositides. Synaptojanins combine this activity with an additional Sac1-like phosphatase region and regulatory domains. Different family architectures target distinct lipid pools and cellular trafficking events.

KH-domain RNA-binding proteins in this family regulate RNA maturation and expression. SF1/branchpoint-binding proteins recognize intronic branchpoint regions during early spliceosome assembly, whereas STAR/QKI/KHDRBS-related proteins regulate selected RNA targets through alternative splicing and other post-transcriptional mechanisms.

Exportins mediate nuclear export of distinct cargo classes. Exportin-1 recognizes protein export signals, whereas exportin-5 and related receptors export structured RNAs and selected other cargos.

Cyclic-nucleotide phosphodiesterases terminate or shape second-messenger signals by hydrolyzing cyclic nucleotides. Members differ in cAMP versus cGMP preference, dual specificity and regulatory domains. PDE4/Dunce-type enzymes belong to a cAMP-directed branch, distinct from retinal cGMP phosphodiesterases.

Nucleoside diphosphate kinases redistribute terminal phosphate among nucleotide pools through a phosphohistidine intermediate. The Awd/NM23-type catalytic role contributes to nucleotide homeostasis, while individual proteins can also participate in trafficking and developmental regulation. Those cellular roles need not imply a different phosphotransfer reaction.

Core membrane subunit family of the proton-pumping NADH:quinone oxidoreductases: bacterial NuoH, mitochondrial ND1, and the plastid-encoded NdhA of the chloroplast NDH complex. Bacterial and mitochondrial members are respiratory, oxidizing NADH and reducing ubiquinone in NDH-1 or respiratory complex I during aerobic respiration. The plastid NdhA clade belongs to the thylakoid NAD(P)H dehydrogenase complex (GO:0010598), which runs photosynthetic cyclic electron flow around photosystem I and chlororespiration and reduces plastoquinone. PAINT already scopes the complex-term assertions in this family to taxon-restricted nodes; the remaining family-level assertions of respiratory process and NADH-donor activity still leak into the plastid clade.

Aromatic amino-acid hydroxylases use reduced pterin and oxygen to hydroxylate aromatic substrates. Phenylalanine hydroxylase produces tyrosine, tyrosine hydroxylase produces L-DOPA and tryptophan hydroxylase produces 5-hydroxytryptophan. These homologous reactions feed different metabolic and signaling pathways.

Animal-type heme-peroxidase relatives use or resemble enzymes that use peroxide in diverse extracellular reactions. Thyroid hormone synthesis, antimicrobial oxidant production, chorion modification and extracellular matrix cross-linking are distinct physiological contexts. Additional extracellular domains and active-site integrity are essential for distinguishing these roles.

Small family of type I transmembrane immunoglobulin-superfamily co-receptors of T lymphocytes, comprising the activating costimulatory receptor CD28 (subfamily SF7) and the inhibitory checkpoint receptor CTLA-4 (subfamily SF8). Members share the same architecture (a single extracellular IgV domain carrying the MYPPPY ligand-binding motif, a transmembrane segment, and a short cytoplasmic tail), form disulfide-linked homodimers, sit on the external side of the plasma membrane, and bind the same two B7 ligands, CD80 (B7-1) and CD86 (B7-2), on antigen-presenting cells. What they do with that shared ligand engagement is opposite. CD28 delivers "signal 2": its cytoplasmic YMNM and PYAP motifs recruit PI3K and GRB2/Lck, amplifying TCR signaling and driving IL-2 production, T cell proliferation and activation (coreceptor activity, GO:0015026). CTLA-4 binds the same ligands with higher avidity and shuts costimulation down: it acts as a ligand-sequestering decoy (receptor decoy activity, GO:0140319), removes CD80/CD86 from APCs by transendocytosis, and its YVKM motif recruits phosphatases that attenuate TCR-proximal signaling (PMID:11279501, PMID:11279502). The family is therefore an object lesson for phylogenetic propagation: ligand, topology, localization and direction-neutral pathway-participation terms are conserved family-wide, while every signaling-direction term (costimulation, positive/negative regulation of T cell activation or proliferation, and the two opposite molecular-function terms) is safe only within one subfamily. InterPro (IPR040216) counts 1947 proteins in 3 subfamilies across 2257 taxa; the reviewed slice contains only mammalian/avian CD28 (SF7) and mammalian CTLA4 (SF8) orthologs, so the third subfamily (the broader family is usually described as also containing the ICOS-like activating receptors) is not represented among reviewed members and is not adjudicated here.

Small heat-shock proteins and alpha-crystallins form oligomeric assemblies that interact with non-native proteins. Client recognition, oligomer structure, expression response and cellular localization vary among organisms and paralogs.

This family combines cytoplasmic tyrosyl-tRNA synthetases with related tRNA-binding or regulatory proteins, including AIMP1-type factors. Complete TyrRS enzymes activate tyrosine with ATP and transfer it to cognate tRNA. Shared ancillary RNA-binding domains do not confer that aminoacylation reaction on a protein lacking the synthetase module.

Tubulin-family GTP-binding proteins form or organize microtubule structures. Alpha/beta heterodimers make the microtubule lattice, whereas gamma-tubulin supports nucleation and other tubulin classes have specialized centriole or basal-body roles. Isotype-specific expression and lattice properties add a further level of divergence.

GPX-fold proteins reduce peroxide substrates using distinct electron-donor systems. The family includes glutathione-dependent enzymes, thioredoxin-supported enzymes, cysteine and selenocysteine forms, and specialized secretory-pathway members.

A metallo-phosphomonoesterase family that hydrolyses phosphate monoesters at alkaline pH through a covalent phosphoseryl intermediate, present from bacteria to vertebrates. Catalysis is carried out by a trinuclear metal centre of two Zn(2+) and one Mg(2+) together with an invariant active-site serine, and every reviewed member of the family retains that serine in an essentially unchanged D-S-A/G context. There is no known pseudo-enzyme branch here: unlike families where a catalytic residue has been lost in one lineage, this one has kept its chemistry intact everywhere it has been examined. What has diverged is not the reaction but where it is performed and what it is performed on. Bacteria secrete the enzyme into the periplasm for phosphate scavenging; fungi relocated it to the vacuole membrane; animals bolted it to the outer leaflet of the plasma membrane through a C-terminal GPI anchor, making it an ectoenzyme that acts on extracellular substrates. Animals also gained a structural Ca(2+) site and a crown domain that have no counterpart in the bacterial enzyme. In bony vertebrates the tissue-nonspecific branch was then recruited to skeletal mineralization, where it destroys extracellular pyrophosphate, and the tissue-specific branch duplicated into the intestinal, placental and germ-cell isozymes. The family is therefore a case where an IBA for the molecular function is safe everywhere and IBAs for compartment and process are safe only within their own clades -- which is exactly how PAINT has scoped them.

PTHR11610 collects the animal lipases built on the pancreatic-lipase fold: an N-terminal alpha/beta-hydrolase catalytic domain carrying a Ser-Asp-His triad under a mobile surface "lid", plus a C-terminal PLAT/beta-sandwich domain that mediates interfacial and cofactor interactions. All members are secreted and all are ester hydrolases acting at a lipid-water interface, which is what the deep PAINT node PTN008325466 records (lipase activity, lipid catabolic process, extracellular region) and what is genuinely shared. Above that shared floor the family splits into groups whose substrates, cofactors and anatomical compartments are different. The exocrine pancreatic branch (PNLIP, PNLIPRP1, PNLIPRP2) is secreted into the gut lumen, hydrolyses emulsified dietary triacylglycerol, and depends on colipase to work in the presence of bile salts. The vascular branch (lipoprotein lipase, hepatic lipase, endothelial lipase) is heparan-sulfate-anchored at the endothelial surface, acts on triacylglycerol and phospholipid carried in circulating lipoprotein particles, uses apolipoprotein cofactors such as apoC-II, and is the branch that remodels VLDL, chylomicrons and HDL. A third branch (LIPH, LIPI, PLA1A) has specialised as phospholipases A1 that generate lysophospholipid signalling molecules. Chimera experiments locate much of the triacylglycerol-versus-phospholipid preference in the lid rather than in the triad, so substrate specificity in this family is a surface property of an otherwise conserved catalytic machine. A consequence that matters for annotation: catalytic-residue loss is not the discriminator anywhere in this family. Every member checked here retains an intact Ser-Asp-His triad, including human PNLIPRP1, which is named "inactive" and has no demonstrated lipase activity. Differences between the branches therefore have to be argued from substrate, cofactor and compartment, not from a degraded active site.

NARF and NARFL/Nar1-related proteins illustrate functional divergence among hydrogenase-related proteins. Human NARF binds prenylated prelamin A, whereas NARFL/IOP1 has direct support in cytosolic iron-sulfur protein maturation. Broad structural relationships do not establish respiratory hydrogenase chemistry or identical Fe-S assembly roles.

MCM-family ATPases include the MCM2-7 replicative helicase subunits and MCM8/9-associated DNA repair factors. Eukaryotic MCM2-7 functions as a heterohexamer within the active replisome, with different subunits contributing to an assembled motor. Related MCM8/9 proteins do not simply substitute for replication-licensing subunits.

Immunoglobulin-domain extracellular and cell-surface proteins in this grouping mediate adhesion, recognition or tissue organization. The nephrin/Sns branch contributes to specialized cell junctions and, in flies, myoblast recognition and fusion. Other branches include different adhesion receptors and larger extracellular matrix proteins.

Cytidine-deaminase-related proteins use a zinc-dependent deamination scaffold with divergent substrates. The grouping includes conventional nucleoside deaminases and blasticidin-S deaminases, as well as plant relatives whose catalytic competence is uncertain.

Clamp-loader-related ATPases assemble sliding clamps on nucleic acids to support processive DNA synthesis and repair. Eukaryotic RFC complexes combine several small subunits with alternative large subunits; related bacterial clamp-loader components and plant Stichel proteins broaden the family beyond one canonical replication complex.

The aldehyde dehydrogenases share a conserved three-domain architecture -- a Rossmann-fold NAD(P)+-binding domain, a catalytic domain, and a smaller oligomerization domain -- and oxidize aldehydes to their carboxylic acids through a covalent thio(hemi)acetal intermediate formed at a catalytic cysteine nucleophile, with a conserved glutamate acting as general base. The family is old and broad: the deepest cached PAINT node for NAD+-dependent aldehyde dehydrogenase activity is seeded by bacterial, fungal, plant and animal members, and 47 PANTHER subfamilies span substrate specialists as different as retinaldehyde dehydrogenases (the ALDH1A/RALDH branch, source of embryonic retinoic acid), mitochondrial acetaldehyde-preferring ALDH2, betaine-aldehyde and succinate-semialdehyde dehydrogenases, acylating acetaldehyde dehydrogenases (EutE), 10-formyltetrahydrofolate dehydrogenase fusion proteins (ALDH1L), and at least one member with degenerate active-site residues (ALDH16A1). The ALDH1L proteins are multidomain fusion enzymes: an N-terminal folate-binding hydrolase/formyltransferase-like domain and a 4'-phosphopantetheine carrier domain deliver the formyl group of 10-formyl-THF to a C-terminal ALDH domain that oxidizes it to CO2 using NADP+, not NAD+; vertebrates carry a compartment-split ALDH1L paralog pair -- cytosolic ALDH1L1 and mitochondrial ALDH1L2, the latter distinguished by an N-terminal mitochondrial transit peptide acquired in its own lineage. Generic aldehyde-oxidation chemistry is close to family-wide; substrate identity, cofactor preference (NAD+ vs NADP+), localization and pathway context are not, and are the properties that distinguish subfamilies -- which is why family- or deep-node-level propagation of NAD+ cofactor terms or of a compartment term is unsafe even though the catalytic fold and the Cys/Glu machinery are conserved.

NRAMP/SLC11 proteins are proton-coupled divalent metal transporters found across bacteria, fungi, plants and animals. Characterized members move Fe(2+), Mn(2+) and other divalent cations across plasma, endosomal or vacuolar membranes: human SLC11A2 (DMT1) mediates dietary iron uptake and endosomal iron export, human SLC11A1 acts in phagosomal metal handling, yeast SMF1/SMF2 transport manganese, and plant NRAMPs (Arabidopsis NRAMP1-6, poplar NRAMP1-7) mobilize iron and manganese between the vacuole, plastids and the cytosol. One clade is not a transporter at all. The land-plant EIN2 proteins (subfamily SF75) carry an NRAMP-like N-terminal integral-membrane domain but have appended a large C-terminal cytoplasmic extension, roughly doubling the protein length (the reviewed transporter subfamilies run 500-581 aa in the fetched slice, all non-EIN2 members 397-696 aa; EIN2 members run 1281-1294 aa). EIN2 is the central transducer of ethylene signaling at the endoplasmic reticulum membrane: ethylene perception triggers cleavage and nuclear/cytoplasmic translocation of its C-terminal fragment. No metal transport activity has been demonstrated for any EIN2, so transport and metal-homeostasis terms placed on deep family nodes must not descend into SF75.

PTHR11711 collects the ADP-ribosylation factor (Arf) and Arf-like (Arl) small GTPases, a large branch of the Ras superfamily built on a P-loop G domain plus an N-terminal amphipathic helix that is myristoylated or acetylated and inserts into membranes when the protein is GTP-loaded. Members are not enzymes acting on a diffusible substrate: the conserved chemistry is the nucleotide cycle itself, and the biological output is the recruitment of effectors to a particular membrane. Intrinsic hydrolysis is slow and is completed by ArfGAPs, which supply an arginine finger in trans, so the G domain encodes the switch but not a fast turnover rate. The family name is historical -- Arf was named as a cofactor for cholera-toxin-catalysed ADP-ribosylation, not because its members ADP-ribosylate anything -- which is why a preferred_name is recorded alongside it. What differs between members is where the switch operates. The classical ARFs (ARF1-5) act at the Golgi and drive COPI and clathrin-adaptor recruitment; ARF6 works at the plasma membrane and endocytic compartments; ARL1 marks the TGN for golgin tethers; the ARL5 clade acts at the TGN, where it is recruited downstream of ARFRP1-SYS1 and in turn recruits the GARP tethering complex and the ARMH3-PI4KB module for endosome-to-TGN retrograde traffic; and ARL6/BBS3 has moved out of the secretory pathway altogether into BBSome-dependent ciliary transport. Nucleotide-binding terms are therefore safe across the whole family while compartment terms are not.

Beta-ketoacyl synthases extend acyl chains by condensation with activated malonyl donors. Related enzymes serve bacterial and organellar fatty-acid synthesis as well as specialized polyketide pathways. Product length and pathway context depend on the enzyme and its surrounding biosynthetic machinery. Related noncatalytic chain-length factors partner with the catalytic ketosynthase in aromatic polyketide synthesis.

NAD(P)-dependent glycerol-3-phosphate dehydrogenases interconvert dihydroxyacetone phosphate and glycerol-3-phosphate while coupling to pyridine-nucleotide redox chemistry. Related paralogs serve glycerolipid metabolism, redox shuttling or lineage-specific glycerol production. They are distinct from the FAD-dependent mitochondrial shuttle enzyme.

M13 metallopeptidase relatives include neprilysins, endothelin-converting enzymes, PHEX and other extracellular or membrane-associated proteins. Characterized enzymes share a zinc-dependent proteolytic framework while differing substantially in peptide substrate selection and biological role.

Class I alpha-mannosidases trim alpha-1,2-linked mannose residues from N-linked glycans. Related enzymes act at different stages of secretory-pathway glycan maturation and quality control. Their location and preferred glycan branch determine whether a particular trimming event supports productive maturation or disposal of a substrate.

Sigma adaptins are small subunits of heterotetrameric adaptor complexes involved in membrane cargo sorting. AP-1, AP-2, AP-3 and AP-4 complexes use related sigma subunits at different membrane compartments. Their shared structural role does not identify a single vesicle destination.

The NADH-oxidising flavoprotein of the proton-pumping NADH:quinone oxidoreductases: bacterial NuoF (Nqo1 in Paracoccus) and mitochondrial NDUFV1. It sits at the matrix-facing tip of the peripheral arm, binds one non-covalently bound FMN and one [4Fe-4S] cluster (N3), and is where the whole enzyme begins: NADH docks on a glycine-rich loop, transfers a hydride to FMN, and the reduced flavin passes electrons one at a time to N3 and onward down the iron-sulfur wire to the quinone chamber built by the 49 kDa subunit family (PANTHER:PTHR11993). The reduced flavin is also the principal site at which complex I leaks electrons to oxygen, so this subunit carries the enzyme's superoxide chemistry as well as its productive chemistry. The family is strikingly uniform: in the fetched slice, alphaproteobacterial, actinobacterial, fungal, plant, amoebozoan and animal members all carry the same four N3 cysteine ligands and the same NADH-binding glycine loop, and there is no organellar or photosynthetic branch - the plastid NDH complex has no counterpart of this subunit at all, which is precisely why that complex is reduced by ferredoxin rather than by NADH.

NTPDase/apyrase-related enzymes hydrolyze nucleoside di- and triphosphates. Members operate extracellularly or in secretory compartments, with different preferences for ATP, ADP, UDP, GDP and other nucleotides. These differences connect the family to either extracellular nucleotide signaling or organellar glycosylation and nucleotide metabolism.

SLC26/SulP proteins share a membrane transport fold and commonly a STAS domain. Members transport different anions with different coupling modes; the family also includes the specialized mammalian prestin motor.

Voltage-gated calcium-channel beta subunits are cytosolic auxiliary proteins that regulate channel assembly, trafficking and gating through interaction with pore-forming alpha1 subunits. Their SH3/guanylate-kinase-like architecture supports protein interactions. It does not create a calcium-conducting pore or establish guanylate-kinase catalysis.

Branched-chain amino-acid aminotransferases reversibly exchange amino groups between branched-chain amino acids and their ketoacids using pyridoxal phosphate. Cytosolic, mitochondrial and microbial members retain related chemistry while serving different metabolic directions and compartments.

This membrane oxidoreductase grouping includes cholesterol hydroxylases, sterol desaturases and other lipid-modifying enzymes. CH25H converts cholesterol to 25-hydroxycholesterol, a reaction distinct from sterol C4 demethylation or introduction of a sterol double bond. Related metal-dependent architectures do not make these reactions interchangeable.

Glyoxalase-II-related metallohydrolases include hydroxyacylglutathione hydrolases and divergent PNKD proteins. Classical glyoxalase II hydrolyzes S-lactoylglutathione in methylglyoxal detoxification. Human PNKD-L shows very low turnover of this substrate and fails to restore its metabolism in a fly HAGH-null background, establishing a functional boundary despite the related fold.

UDP-sugar pyrophosphorylase relatives activate sugar phosphates with UTP to supply nucleotide-sugar donors. UAP1-type proteins act on N-acetylhexosamine phosphates, while other branches use different sugars. The identity and stereochemistry of the sugar phosphate determine the biochemical annotation.

NADPH oxidase and ferric-reductase relatives transfer electrons across membranes through flavin and heme cofactors. NOX/DUOX branches generate reactive oxygen species, whereas ferric reductases reduce extracellular or organellar metal substrates. DUOX proteins additionally carry extracellular peroxidase-like regions and calcium-responsive regulatory elements.

The large "49 kDa" subunit that forms the quinone-reduction chamber of every proton-pumping NADH:quinone oxidoreductase and of the plastid NDH complex. Members are bacterial NuoD (often fused to NuoC as a single NuoCD chain), mitochondrial NDUFS2 and its organelle-encoded plant counterpart NAD7, and the plastid-encoded NdhH of the thylakoid NAD(P)H dehydrogenase complex. The subunit descends from the large subunit of [NiFe] hydrogenase and retains that fold, but the metal site is vestigial: no structure of bacterial, mitochondrial or plastid complex I places an iron-sulfur cluster on it, and the terminal N2 cluster that delivers electrons into the quinone site is held by the neighbouring NuoB/NDUFS7 subunit instead. What the subunit does contribute, family-wide, is the amphipathic quinone channel and the invariant His/Tyr pair at its mouth that hydrogen-bonds the quinone headgroup. The identity of that quinone is where the family divides: ubiquinone or menaquinone in the respiratory members, plastoquinone in the plastid NdhH clade, whose complex is reduced by ferredoxin rather than by NADH and runs cyclic electron flow around photosystem I rather than respiration.

Homologous subunits of respiratory complex I and chloroplast NDH: NuoB / mitochondrial NDUFS7 / plastid NdhK. Respiratory complexes receive electrons from NADH, whereas the chloroplast NDH complex lacks the NADH-oxidizing module and uses reduced ferredoxin to reduce plastoquinone. Coupled proton translocation is conserved. The chloroplast complex contributes to cyclic photosynthetic ATP production and has evidence for chlororespiratory participation; chloroplast localization does not by itself negate respiratory process terms.

CNNM/ACDP proteins contain a membrane region and cytosolic regulatory architecture associated with metal-ion homeostasis. Mammalian CNNMs and fungal or plant homologs differ in membrane destination and physiological context.

FCP/SCP-like phosphatase-domain proteins in this family serve distinct cellular roles. CTD small phosphatases such as CTDSP2 dephosphorylate protein substrates associated with transcriptional regulation, whereas TIM50-family proteins participate in mitochondrial precursor import. Shared phosphatase-like architecture does not make all members mitochondrial translocase subunits.

This membrane-protein grouping includes fly Headbutt and Rolling stone in distinct subfamilies, alongside plant membrane-protein descriptors. Rolling stone is required for myoblast fusion; no common transport reaction or lipid substrate is established across the grouping.

ABT1/Esf2 proteins are nuclear interaction factors linked to RNA production and ribosome biogenesis. Yeast Esf2 binds pre-rRNA, participates in U3/90S small-subunit biogenesis and stimulates the helicase Dbp8. The conserved molecular role is better defined by these RNA-processing interactions than by a generic transcription-associated name.

Importin-beta-like receptors bind selected cargoes and mediate nucleocytoplasmic transport. This family includes importin-13 and transportin-3/Mtr10-related branches, with different cargo preferences and potentially different transport directions for particular substrates. Ran-dependent cargo exchange couples transport to the nuclear compartment.

EFR3 proteins anchor phosphatidylinositol-4-kinase-associated assemblies at the plasma membrane. Their conserved role is recruitment and organization of a lipid-kinase complex, allowing membrane phosphoinositide synthesis to occur at the correct location. EFR3A and EFR3B represent closely related mammalian branches.

NOL4-family proteins are nuclear interaction proteins with isoform-dependent regulatory activities demonstrated in mammals. Mouse NOL4 splice variants bind the Mlr1/Mlr2 transcription factors and alter their transcriptional output; the conserved molecular role of the divergent fly CG46301 product remains unresolved.

FAM20 proteins share a secretory-pathway kinase-like architecture but diverge in catalytic output. FAM20B phosphorylates xylose in the glycosaminoglycan linkage region; FAM20C phosphorylates secreted proteins; FAM20A is a regulatory pseudokinase that supports FAM20C function. Sugar phosphorylation and protein phosphorylation are distinct activities.

SDHAF2/Sdh5/SdhE proteins promote maturation of the succinate-dehydrogenase flavoprotein, particularly covalent flavinylation. They help establish a catalytically competent flavoprotein rather than serving as the respiratory substrate-oxidizing enzyme. The same assembly principle spans mitochondrial and bacterial systems.

This family includes JMJD4, JMJD6, JMJD8 and plant JMJ20/JMJ22-like proteins. JmjC architecture unites the group but does not establish a common substrate, chromatin role or developmental pathway.

ENY2/Sus1 proteins couple transcription and nuclear mRNA export through membership in SAGA and TREX-2. Within SAGA they support the histone H2B deubiquitination module; within TREX-2 they help connect export machinery to the nuclear pore. These are small noncatalytic complex subunits, so SAGA membership does not confer intrinsic histone acetyltransferase or deubiquitinase activity.

This family contains glycerol-3-phosphate acyltransferases and dihydroxyacetone phosphate acyltransferases, which initiate different branches of glycerolipid synthesis. Human GPAM/GPAT1 transfers an acyl group to glycerol-3-phosphate at the mitochondrial outer membrane. Its experimentally determined membrane association uses an amphipathic surface rather than the transmembrane topology formerly proposed.

CPEB proteins bind regulatory elements in mRNA 3-prime untranslated regions and control translation through cytoplasmic polyadenylation and repression mechanisms. Their conserved RNA-binding region combines RNA recognition motifs with a zinc-binding domain. Orb and the CPEB paralogs have different mRNA targets and developmental deployments, while the shared activity is post-transcriptional regulation rather than transcription factor activity.

PHRF1-related PHD/RING proteins include poorly characterized eukaryotic interaction proteins and a Komagataella micropexophagic-apparatus component catalogued as Atg36/Atg35. Shared zinc-binding domains do not establish identical ubiquitin-ligase substrates or a conserved autophagy-receptor mechanism.

NF-YA/Hap2 proteins form the sequence-recognition component of the heteromeric CCAAT-binding transcription factor. DNA binding and transcriptional regulation depend on assembly with the other NF-Y subunits. Fungal iron and oxidative-stress responses and plant developmental functions represent deployment of this conserved transcriptional machinery in different regulatory networks.

Pan-eukaryotic family of integral peroxisomal membrane proteins that drive peroxisome proliferation by the growth-and-division pathway: they deform and elongate the peroxisomal membrane and coordinate recruitment of the shared fission machinery (FIS1/MFF and the dynamin-related GTPase DRP1/DNM1L/Dnm1) to complete organelle division. The fetched reviewed slice spans fungi (S. cerevisiae PEX11/PMP27 and the divergent paralog PEX25, Candida boidinii PMP30A/B, S. pombe pex11), plants (Arabidopsis PEX11A-E, rice PEX11-1..5), amoebozoa (Dictyostelium pex11) and animals (mammalian PEX11A and PEX11B). Human PEX11B (the family's best-characterized mammalian member) is the constitutive driver of peroxisome fission: its overexpression alone induces peroxisome proliferation, its N-terminal domain mediates the homo-oligomerization required for membrane elongation, and it forms ternary complexes with FIS1 and DLP1. Note that human PEX11G is NOT in this family — the PANTHER member index places Q96HA9 in PTHR20990 — so the family's human members are PEX11A (SF22) and PEX11B (SF7) only.

GBA2 proteins hydrolyze glucosylceramide outside the lysosomal GBA pathway. Human isoform-expression experiments show strong activity and altered ceramide balance for isoform 1, whereas the other tested isoforms had activity near background. An assignment of the family therefore supports a glycosphingolipid-metabolism hypothesis but is insufficient to declare every alternative protein record catalytically active.

Small (about 150-220 aa), deeply conserved family of multi-pass ER membrane proteins comprising yeast Orm1/Orm2, plant ORM proteins, insect ORMDL and the three vertebrate paralogs ORMDL1/2/3. All characterized members are stoichiometric regulatory subunits of the serine palmitoyltransferase (SPT) complex, the first and rate-limiting enzyme of de novo sphingolipid biosynthesis, and act as its sphingolipid-responsive negative regulators: the ORMDL N-terminus occludes the SPT substrate entry tunnel, and ceramide binding stabilizes this inhibitory conformation, implementing a homeostatic negative feedback loop. The functional equivalence across the family is experimentally direct — human ORMDL3 rescues the yeast orm1/orm2 double mutant, and triple knockdown of ORMDL1/2/3 in HeLa cells raises ceramide about three-fold. Human ORMDL3 (17q21) is additionally the strongest replicated childhood-asthma GWAS locus, but its immune phenotypes are downstream of the conserved sphingolipid-regulatory job. The family is a textbook case where family-wide propagation of the SPT-complex and sphingolipid-homeostasis terms is safe.

Rpf2 proteins are conserved Brix-domain ribosome assembly factors. Together with Rrs1 and ribosomal proteins, they participate in incorporation and maturation of the large-subunit ribonucleoprotein particle. Their role is RNA binding and preribosome assembly rather than peptide synthesis or an intrinsic rRNA-processing nuclease reaction.

Pan-eukaryotic family of C-terminal SUN-domain proteins. These are type II integral proteins of the inner nuclear membrane. Each has a nucleoplasmic N-terminal region that binds lamins or chromatin/telomere/centromere partners, a transmembrane segment, luminal coiled coils that trimerize, and a C-terminal SUN domain in the perinuclear space. The SUN domain binds the C-terminal KASH (or KASH-like) peptides of outer-nuclear-membrane proteins. The resulting SUN-KASH bridges (LINC complexes) span the nuclear envelope and couple the nucleoskeleton and chromosomes to cytoskeletal force. The family covers: (1) Vertebrate SUN1 (SF23) and SUN2 (SF22). These are ubiquitous somatic LINC anchors for nesprins in nuclear positioning, nucleokinesis and mechanotransduction. SUN1, and SUN2 in part, also pairs with KASH5 to tether meiotic telomeres. (2) An amniote testis-specific clade: SUN3 (SF24), SPAG4/SUN4 (SF16) and SUN5 (SF44). These form spermiogenesis-specific LINC complexes that shape the sperm head and anchor the head-tail coupling apparatus after meiosis. (3) Nematode paralogs that split the ancestral roles. UNC-84 (SF8) is the somatic anchor for UNC-83 (microtubule-motor nuclear migration) and ANC-1 (actin-based nuclear anchorage). SUN-1 (SF2) is the meiotic and embryonic partner of ZYG-12. (4) Drosophila Klaroid (SF8), the SUN partner of Klarsicht and Msp300 in nuclear migration, myonuclear positioning and germline centromere pairing. (5) The single fungal SUN proteins Sad1 (fission yeast) and Mps3 (budding yeast), both SF8. These anchor the spindle pole body to the nuclear envelope with KASH or KASH-like partners (Kms2, Mps2) and form meiotic telomere-bouquet LINC complexes (Sad1-Kms1; Mps3-Mps2-Csm4). (6) Plant Cter-SUN proteins (Arabidopsis SUN1 in SF8, SUN2 in SF47). They anchor plant-specific KASH proteins (WIP, SINE, TIK) and couple the nucleus to actin via WIT2-myosin XI-i. They also act in meiotic telomere attachment. The SUN-KASH anchoring activity and nuclear-envelope location are conserved across the family. The kind of cytoskeleton coupled (microtubules, actin, the spindle pole body) and the cell-cycle context (somatic, meiotic, spermiogenic) differ between lineages.

PIGT/Gpi16 proteins are components of the endoplasmic-reticulum GPI transamidase complex that attaches glycosylphosphatidylinositol anchors to proteins. Complex membership explains participation in the attachment reaction, while the catalytic chemistry belongs to the assembled machinery and its catalytic subunit. PIGT is not a generic soluble protease simply because the complex processes a protein precursor.

SPCS2/Spc2 proteins are membrane-associated accessory components of the eukaryotic signal peptidase complex. They promote complex activity and coordination with protein translocation, while SEC11-related subunits supply signal-peptide cleavage catalysis.

Cystinosins are membrane proteins that export cystine from the lysosomal or vacuolar lumen. The experimentally annotated Drosophila Ctns record supports a cystine/proton transport function and a role in maintaining cysteine availability during fasting. Effects on mTORC1, autophagy and metabolism follow from this transport role and are not independent transport substrates.

TRUB2-related proteins are associated with mitochondrial RNA pseudouridylation. Family membership supports an RNA-modification hypothesis but does not identify the RNA substrate or guarantee catalytic competence of a fragment.

Dolichol kinases phosphorylate the polyprenol carrier used in protein glycosylation and GPI-anchor synthesis, using CTP as donor. The integrated InterPro group also includes plant phytol kinases involved in tocopherol biosynthesis. The lipid substrate and metabolic pathway therefore need to be resolved independently of the shared membrane-associated kinase architecture.

KRIT1 and FRMD8 are FERM-domain interaction proteins with distinct partners. KRIT1 participates in the cerebral cavernous malformation signaling machinery and stabilizes endothelial junctions. FRMD8 binds iRhom proteins and protects the iRhom/ADAM17 sheddase complex from endolysosomal degradation, sustaining inflammatory and growth-factor ligand release.

Family of Pex16/peroxin-16, one of the three "early" peroxins - with Pex3 and Pex19 - that build the peroxisomal membrane rather than filling it. Pex16 is an integral membrane protein with two transmembrane segments and both termini facing the cytosol. In mammals it is inserted cotranslationally into the ER, exported through Sec16B-dependent ER exit sites, and acts at the peroxisomal membrane as the anchoring receptor for Pex3, holding the Pex3-Pex19 carrier where newly synthesised peroxisomal membrane proteins can be delivered. Its loss is unusually severe among the peroxins: PEX16-deficient patient cells have no detectable peroxisomal membranes at all - not even the "ghosts" seen in matrix-import mutants - and re-expressing PEX16 rebuilds peroxisomes de novo, with membrane protein import preceding matrix protein import. Matrix import failure in PEX16-null cells is therefore a downstream consequence of having no organelle, not a function of Pex16. The family spans eukaryotes - the fetched slice runs from Yarrowia and S. pombe through Dictyostelium and Arabidopsis to fish, frog and mammals - and all reviewed members sit in a single subfamily. Taxonomic coverage in fungi is patchy, and at least one yeast lineage performs the equivalent ER-to-peroxisome PMP trafficking step with a non-orthologous protein (Pex36), so the family does not coincide with the function.

Plant cellulose synthases and related glycosyltransferases synthesize different glycan products. The retrieved group contains cellulose synthases, mixed-linkage glucan synthases and specialized small-molecule glycosyltransferases; the PANTHER X-box transcription-factor label is misleading for these members.

Members include bacterial rRNA methyltransferase RlmF, eukaryotic METTL16/U6 RNA methyltransferases and psilocybin synthase PsiM proteins. METTL16-dependent U6 modification connects RNA methylation to splicing; vertebrate MAT2A regulation is an additional regulatory deployment. Neither a U6 substrate nor RNA methylation itself follows automatically from this broad PANTHER assignment.

RPC4/C53 proteins are noncatalytic subunits of RNA polymerase III. They help organize the transcription complex and its initiation, termination and reinitiation behavior through association with other polymerase subunits. Participation in RNA synthesis does not mean that an isolated RPC4 protein catalyzes phosphodiester-bond formation.

Proteinaceous RNase P proteins use an RNA-recognition region and a nuclease domain to remove precursor tRNA 5-prime leaders. Plant PRORPs and animal mitochondrial RNase P catalytic subunits differ in compartment and partner dependence.

Fritz/WDPCP proteins organize cytoskeletal and membrane-associated machinery involved in cell polarity and ciliogenesis. Mammalian WDPCP participates in the CPLANE machinery that recruits intraflagellar transport components, while fly Fritz is associated with patterned wing-cell protrusions. These are related cellular organization functions, not evidence for a catalytic activity encoded by the WD-repeat fold.

ESRP and hnRNP H/F-related proteins use RNA-recognition motifs in transcript processing and regulation. The retrieved family also includes GRSF1 and other RNA-binding proteins with distinct RNA targets and subcellular destinations.

Spt16 is the large subunit of FACT, a histone chaperone that reorganizes nucleosomes while preserving chromatin integrity. Its amino-terminal aminopeptidase-like fold binds histones H3 and H4. Structural and biochemical work on pombe Spt16 establishes a nonenzymatic histone-binding function for that fold, rather than aminopeptidase catalysis.

AFAP1, AFAP1L1 and AFAP1L2/XB130 are PH-domain-containing adaptor proteins associated with actin and membrane signaling. Their interaction regions recruit different signaling partners rather than catalyzing a shared chemical reaction. AFAP1L2 evidence for signal transduction should be interpreted in the context of that paralog's architecture and partners.

Rpa49 is an accessory subunit of RNA polymerase I that supports efficient ribosomal DNA transcription. The polymerase can retain activity when Rpa49 is deleted, indicating a stimulatory and organizational role rather than independent RNA polymerase catalysis. Its conserved function is linked to the specialized rRNA transcription machinery.

SHLD2 is a component of shieldin, a DNA-end protection complex acting in double-strand-break repair. Its DNA-associated and complex-assembly functions regulate access of repair machinery to damaged DNA. Shieldin participation is mechanistically distinct from DNA synthesis, helicase activity or nuclease activity.

Deuterostome family of giant spectrin-repeat proteins. It covers two chordate lineages that arose by a duplication (PANTHER node PTN000376568), plus a single-copy sea-urchin KASH protein. (1) The nesprin lineage has the vertebrate paralogs nesprin-1 (SYNE1, SF3) and nesprin-2 (SYNE2, SF4). These are the giant KASH proteins of the outer nuclear membrane. Their C-terminal KASH peptide binds SUN1/SUN2 trimers in the perinuclear space to form LINC complexes. Their N-terminal calponin-homology domains bind F-actin, and their spectrin-repeat rods recruit dynein-dynactin (via BICD2) and kinesin-1. In this way they anchor the cytoskeleton to the nuclear envelope and transmit the forces for nuclear migration, nuclear anchorage and centrosome-nucleus coupling. (2) The AKAP6 lineage (SF2, muscle A-kinase anchoring protein, mAKAP) is a PKA-anchoring signalling scaffold of the cardiac-myocyte nuclear envelope and sarcoplasmic reticulum. It organizes PKA, RyR2, PDE4D3 and PP2A. No vertebrate AKAP6 examined has a KASH domain, and it reaches the nuclear envelope indirectly by binding nesprin-1alpha. The single amphioxus member of the AKAP6 clade and the sea-urchin member (SF7) both keep a KASH domain. PANTHER's family name reflects the AKAP6 lineage only. The core molecular function of the family's best-studied members (nesprin-1/2) is nuclear-envelope cytoskeletal anchoring, not PKA anchoring. Invertebrate nesprin orthologs are classified in other PANTHER families (see notes).

WDR76/CMR1-related WD40 proteins have experimentally supported nuclear/chromatin associations in characterized homologs. Arabidopsis DRS1 has direct drought and ABA-dependent leaf-water-loss phenotypes, while its biochemical connection to chromatin remains unresolved. Broad DNA/chromatin association must be distinguished from a particular modified-base-reader mechanism.

The cached family records group catalytic nucleotide-binding subunits of rotary ATPases, including F-type ATP synthase beta and V-type ATPase A proteins. F-type complexes predominantly synthesize ATP using a proton gradient but retain regulated reverse ATP hydrolysis. Physiological reaction preference therefore cannot be used to reject hydrolysis capacity. Vacuolar localization and functional complex membership require separate phylogenetic and localization evidence. The family also contains the bacterial type III export ATPases (flagellar FliI and injectisome SctN), paralogs of F1-beta that assemble into FliH/FliI/FliJ-type cytoplasmic rings and hydrolyse ATP to release export chaperones and unfold substrates; they have no Fo sector and do not synthesize ATP.

Symplekin and Pta1 are scaffolding components of eukaryotic RNA 3-prime-end processing machinery. They organize cleavage/polyadenylation factors and associated regulatory components. Historical names referring to pre-tRNA processing do not define an intrinsic endonuclease reaction for the family.

DGCR2-related proteins are membrane-associated interaction proteins with extracellular-domain architecture. Mouse DGCR2 participates in cortical-neuron migration and associates with the Reelin signaling complex; the conserved ligand and signaling role of divergent fly CG42404 remain unresolved.

Family of endoplasmic-reticulum-lumenal lectins built around the mannose 6-phosphate receptor homology (MRH) domain: fungal Yos9, plant OS9, and the two vertebrate paralogs OS-9 and ERLEC1 (XTP3-B/Erlectin). Members are soluble, signal-peptide-bearing ER lumen residents that act as glycan-reading substrate receptors in ER-associated degradation (ERAD): the MRH pocket recognizes trimmed high-mannose N-glycans exposing a terminal alpha-1,6-linked mannose on misfolded glycoproteins, and the lectin hands the substrate, via the SEL1L (yeast Hrd3) adaptor, to the HRD1 ubiquitin ligase complex for retrotranslocation and proteasomal degradation. This role is conserved from fungi through plants to vertebrates - the fetched 24-member slice spans yeasts (S. cerevisiae Yos9, S. pombe yos9), filamentous fungi, Arabidopsis and rice OS9, Xenopus and mammals - and the family's PAINT node is accordingly placed at the eukaryote root. Within mammals the two paralogs partition the work with regulatory nuance: OS-9 and ERLEC1 redundantly promote glycoprotein ERAD and stabilize the SEL1L-HRD1 complex, while ERLEC1 additionally restrains degradation of non-glycosylated substrates, an activity OS-9 antagonizes. Domain composition varies (human OS-9 has one MRH domain, ERLEC1 has two, of which only the C-terminal MRH2 is a functional glycan-binding module), but the core function - ER-lumenal misfolded-glycoprotein recognition for ERAD - is uniform.

Pcf11 couples RNA polymerase II termination to pre-mRNA 3-prime-end processing through interactions with the polymerase and cleavage/polyadenylation machinery. Its function depends on a multidomain protein and association with factors such as Clp1. A short fragment matching part of Pcf11 cannot be assumed to carry all functions of the intact protein.

This broad group contains multiple zinc-finger transcription regulators, including Krueppel-like proteins, PLAG proteins and PRDM proteins. Some branches carry additional chromatin-regulatory domains, whereas others primarily recognize DNA through zinc-finger arrays. Drosophila Dati has a demonstrated role in specific neuronal circuits, but this behavior is not a family-wide property.

Classical phospholipase D proteins hydrolyze glycerophospholipids to phosphatidic acid and a released head group. The family includes animal PLD1/PLD2 and multiple plant PLD classes with different regulatory and membrane-interaction features. Lipid hydrolysis is the common mechanistic theme, while stimulus dependence, preferred substrates and cellular signaling outputs vary.

This HAD-like family contains pseudouridine-5-prime-phosphatases, glycerol-3-phosphatases, carbohydrate phosphatases and beta-phosphoglucomutase. The shared fold supports phosphate-group chemistry but does not specify the physiological substrate or distinguish hydrolysis from intramolecular phosphate transfer. Human HDHD1/PUDP is experimentally selective for pseudouridine 5-prime-phosphate.

This family spans DEAH-related helicases with roles in RNA processing, genome defense and other nucleic-acid transactions, as well as viral proteins. Distinct accessory domains and interaction partners determine substrate choice and biological deployment. The YTHDC2 branch couples helicase activity to modified-RNA recognition, but that specialization is not shared by all family members.

This family groups proteins carrying a fibrinogen C-terminal interaction domain, including ficolins, fibroleukin, microfibril-associated proteins and angiopoietin-related proteins. Their functions range from ligand recognition to extracellular structural and signaling roles. The domain name does not imply that every member contributes to fibrin clot formation.

CENP-B-related proteins illustrate evolutionary recruitment of transposon-derived DNA-binding machinery into host chromatin regulation. Pombe Cbh1 binds centromeric repeat DNA, and related pombe proteins participate in retrotransposon silencing and genome organization. The broader group also includes other domesticated transposon-derived regulators, so centromere binding and active transposition are separate hypotheses.

Single-orthologue-group family of Pex13/peroxin-13, the polytopic peroxisomal membrane protein that forms, with Pex14, the docking half of the peroxisomal matrix-protein docking/translocation module (DTM, the "importomer"). Members are present across eukaryotes wherever peroxisomes are - the fetched slice spans yeasts, Dictyostelium, Arabidopsis, nematode, and vertebrates - and the reviewed set falls entirely in one subfamily. The conserved core is the same in all of them: Pex13 sits in the peroxisomal membrane, is part of the importomer, and is required for the docking step at which the cargo-loaded PTS1 receptor Pex5 engages the membrane. Loss of Pex13 abolishes import of both PTS1 and PTS2 matrix cargo while leaving membrane-protein insertion untouched, which is what identifies the defect as receptor engagement rather than membrane assembly. What is not uniform across the family is the domain architecture used to achieve that engagement: a C-terminal SH3 domain that reads the diaromatic WxxxF/Y motifs of Pex5 is described as an opisthokont feature, while the N-terminal YG-rich intrinsically disordered region - now proposed to be the actual translocation conduit, a nucleoporin-FG-like selective phase that Pex5-cargo partitions into - is the more broadly shared element. Family-level compartment and process terms are therefore safe; motif-level molecular function terms are not obviously safe outside the opisthokonts.

The Hsp70/DnaK family comprises ATP-dependent molecular chaperones built from a conserved nucleotide-binding domain allosterically coupled to a substrate-binding domain. All canonical members run the same cycle: ATP-bound low client affinity, J-domain co-chaperone-stimulated hydrolysis, ADP-bound high-affinity client capture, and nucleotide-exchange-factor-driven release. The molecular function is therefore highly conserved from bacterial DnaK to human paralogs. What is NOT shared is the compartment: eukaryotes maintain dedicated paralogs per compartment -- cytosolic and nuclear HSC70/HSP70 (HSPA8, HSPA1A/B, yeast SSA/SSB), the ER-lumenal BiP/GRP78 branch (HSPA5, yeast KAR2), and mitochondrial mortalin (HSPA9, yeast SSC1/SSQ1) -- each routed by N-terminal targeting signals and, for the ER branch, retained by a C-terminal KDEL/HDEL retrieval signal, while cytosolic members instead end in the GPTIEEVD co-chaperone-binding motif. Localization terms are consequently branch-level facts, and the current PAINT slice reflects this: every cellular-component IBD sits on a compartment-specific clade node (cytosol/nucleus on the opisthokont HSC70 node, ER compartments on the BiP node, mitochondrion on the mortalin node), not on the family root.

DCAF11/WDR23 proteins serve as substrate receptors in CUL4-DDB1-associated protein regulation. Direct C. elegans experiments identify SKN-1 and GEN-1 regulatory relationships, with different outcomes for nuclear and cytoplasmic isoforms. The common WD-repeat architecture supports substrate recruitment, while exact substrates and regulatory outcomes cannot be assumed identical across products.

Swd2/WDR82 proteins are WD-repeat components of Set1/COMPASS-associated transcription and chromatin machinery. Fungal proteins can also participate in RNA 3-prime processing complexes. Their presence in a histone methyltransferase complex does not confer methyltransferase catalysis on the WD-repeat protein itself.

This PANTHER group combines coatomer subunits with LIS1/NudF, mitochondrial-division factors and Crt10-related proteins. These proteins use related interaction scaffolds in distinct cellular machines. Budding-yeast Crt10 recruits a cullin-E3 ligase pathway to nonfunctional large-subunit rRNA decay rather than acting as a COPI coat subunit.

eL39 is a small structural protein of the eukaryotic large ribosomal subunit. Its location in the assembled ribosome supports translation and influences the environment encountered by a nascent chain. Its short length is normal for this ribosomal protein family and is not itself evidence of a truncated nonfunctional protein.

CC2D2A participates in the transition-zone machinery that maintains the ciliary membrane as a distinct signaling compartment. Disruption of the complex alters cilia formation and receptor retention. The family also contains CC2D2B-related proteins, whose presence does not by itself establish the same transition-zone role.

This group contains small DUF1091-domain proteins, including fly CG33453. The available sequence-domain assignments establish a conserved protein family but do not identify a biochemical reaction, interaction partner or organelle-specific mechanism. The Daedalus-related name is not a functional assay.

Family of small (~120-290 aa) G-patch-motif proteins orthologous to human GPATCH11, conserved across eukaryotes (InterPro IPR039249; reviewed members span human, mouse, bovine, frog, zebrafish, budding yeast YLR271W and fission yeast SPAC6F6.19/Sap34). The characterized members converge on a single function: regulation of pre-mRNA splicing in or near the early spliceosome. Human GPATCH11 is nucleoplasmic with an additional centrosomal pool, and its biallelic loss-of-function variants cause mis-splicing with early-onset retinal dystrophy and neurological impairment (PMID:39572588); the fission yeast ortholog Sap34 co-purifies with U2 snRNP and U4/U6.U5 tri-snRNP components, contacts the DEAH-box helicase Prp43 through its G-patch domain, and its deletion causes a global splicing defect with increased intron retention (PMID:42260140). The family's historic "CENP-Y" kinetochore association derives from a single low-resolution image in a large-scale mitotic-chromosome proteomic screen (PMID:20813266) and has been contradicted by dedicated localization work; the current PAINT curation has withdrawn it.

Single-subfamily family of CFAP61/FAP61 orthologs, conserved components of the calmodulin- and spoke-associated complex (CSC) of motile cilia and flagella. The CSC (CFAP61 with CFAP91/MAATS1 and CFAP251/WDR66; FAP61/CaM-IP3, FAP91/CaM-IP2 and FAP251/CaM-IP4 in Chlamydomonas) sits at the base of the radial spokes, builds the RS3 stem and connects RS2, RS3 and the nexin-dynein regulatory complex, transducing signals that modulate dynein activity and ciliary/flagellar beating. The function is experimentally established across a very wide phylogenetic span: Chlamydomonas (CSC/radial-spoke assembly and motility), Tetrahymena (RS3 stem assembly, swimming and waveform), and mouse and human (sperm flagellum assembly and flagellated sperm motility; biallelic human loss-of-function causes MMAF/asthenoteratozoospermia, SPGF84). The protein is non-enzymatic; its Rossmann-like FAD/NAD(P)-binding-superfamily fold acts as a structural scaffold. The family distributes across ciliated eukaryotes (2536 proteins, ~4031 taxa in InterPro), consistent with an ancestral motile-cilium axonemal role, and is integrated as InterPro IPR038884.

Tctex-type proteins are small noncatalytic dynein-associated subunits with distinct roles in cytoplasmic and ciliary transport assemblies. DYNLT2B/TCTEX1D2 is an accessory component of dynein-2 required for efficient retrograde intraflagellar transport. ATP-driven motility belongs to the dynein motor machinery rather than the light chain itself.

PPP4R4 proteins are noncatalytic partners of protein phosphatase 4. Human PP4R4 forms a stable cytosolic complex with PP4c that is distinct from other PP4 assemblies and modulates the catalytic subunit’s activity. The regulatory component itself is not a phosphoprotein phosphatase, and its physiological substrate-targeting roles remain incompletely defined.

HID1-family proteins organize Golgi-associated membrane traffic. Mammalian HID1 is a peripheral Golgi protein with N-terminal myristoylation, and a fission-yeast homolog contributes to Golgi organization; specialized dense-core-vesicle functions occur in metazoan cells.

RluA-related enzymes isomerize uridine to pseudouridine in RNA, but family branches act on different rRNAs, tRNAs and other RNA substrates. The inventory includes RluC, RluD, TruC and organellar RNA-modification proteins. Fly RluA-1 and RluA-2 have experimentally demonstrated neuronal phenotypes without those phenotypes identifying their modified RNA nucleotide.

Ubiquitin-specific proteases remove ubiquitin from proteins and ubiquitin chains, with paralog-specific substrate selection and regulatory interactions. USP8/UBPY acts on endosomal ubiquitin dynamics and receptor trafficking. Its deubiquitination can facilitate receptor down-regulation, so ubiquitin removal should not be equated universally with stabilization of the target protein.

Rrp36 proteins participate in early pre-rRNA processing and small-ribosomal-subunit biogenesis. They are preribosomal assembly factors rather than structural constituents of the mature ribosome. A requirement for cleavage at an early processing step does not establish intrinsic nuclease activity.

Xin proteins contain actin-associated repeats and participate in cytoskeletal organization. XIRP1 and XIRP2 share this architectural role while differing in tissue context, binding partners and isoforms.

This group joins related class-II aminoacyl-tRNA synthetases with aspartate or asparagine specificity. Human mitochondrial DARS2 directly catalyzes aspartylation of tRNA and is distinct from the cytosolic translation machinery. Similar catalytic architecture does not establish the same amino acid, tRNA substrate or cellular compartment for every member.

OMA1 is a mitochondrial membrane metalloprotease involved in stress-responsive protein processing. Mammalian OMA1 cleaves OPA1 and participates in pathways that couple mitochondrial damage to cellular responses. Related bacterial proteins act in outer-membrane protein quality control, providing a distinct substrate and compartment context.

Homologous subunits of respiratory complex I and chloroplast NDH: NuoN / mitochondrial ND2 / plastid NdhB. Respiratory complexes receive electrons from NADH, whereas the chloroplast NDH complex lacks the NADH-oxidizing module and uses reduced ferredoxin to reduce plastoquinone. Coupled proton translocation is conserved. The chloroplast complex contributes to cyclic photosynthetic ATP production and has evidence for chlororespiratory participation; chloroplast localization does not by itself negate respiratory process terms.

SAM-dependent RNA cytosine-C5 methyltransferases with branch-specific RNA substrates and nucleotide positions. In fission yeast, Trm4b/Trm402 modifies tRNA C49/C50 in vivo, whereas Trm4a supplies C48 and physiological C34 modification. Trm4b has additional C34 activity on precursor tRNA in vitro; that capability does not establish a physiological C34 role.

RCC1-like repeats occur in HERC ubiquitin ligases, RCC1/BTB proteins, RPGR and secretion-associated exchange-factor architectures. Their common repeat fold does not supply the catalytic domains of these distinct full-length proteins.

DHHC-family proteins catalyze protein S-acylation at membranes. Distinct paralogs act on different protein substrates and membrane compartments. Human ZDHHC23 has evidence for palmitoylation-dependent regulation of KCNMA1 localization, which is a specific substrate relationship rather than a universal property of DHHC enzymes.

CABLES proteins contain a cyclin-like interaction fold and have context-dependent regulatory functions. Fly Cables1 is a basal-body-associated protein required for neuronal and sperm ciliary architecture. Mammalian CDK-associated, cell-cycle and cell-death observations do not establish the same pathways in every CABLES member or imply intrinsic kinase activity.

IKK-related kinases share protein-phosphorylation machinery but act in distinct signaling circuits. Canonical IKK subunits, TBK1 and IKK-epsilon differ in partners and substrates. Fly IKK-epsilon has direct evidence for regulation of actin turnover and polarized morphogenesis, showing that an immune-pathway-only family description is incomplete.

FMO-related proteins catalyze diverse oxidative reactions, including heteroatom oxygenation and specialized-metabolite transformations. The family includes trimethylamine oxidases, thiol-oxidizing enzymes and proteins catalogued as brominating enzymes. Yeast FMO experiments link thiol oxidation to endoplasmic-reticulum redox balance, but that substrate and pathway are not a default for all fungal homologs.

Rhophilin proteins bind Rho-family signaling proteins and organize downstream cytoskeletal interactions. Characterized vertebrate RHPN1 and RHPN2 connect Rho signaling to actin-associated structures. Their role as Rho effectors is distinct from GTP hydrolysis or nucleotide exchange catalyzed by other parts of the signaling system.

Myosin regulatory light chains modulate actomyosin assemblies through association with myosin heavy chains and regulatory phosphorylation. The group contains muscle-specific and nonmuscle paralogs with different expression and contractile contexts. The light chain is not the ATPase motor, and an EF-hand-like fold does not establish equivalent calcium sensing by every paralog.

F-BAR proteins organize membrane-associated assemblies and connect membranes to cytoskeletal or trafficking machinery. The group includes GAS7, PACSIN, PSTPIP, cytokinesis proteins and Rho-GAP-containing proteins with distinct accessory domains.

This family includes active DNMT3 DNA methyltransferases together with regulatory relatives such as DNMT3L and inactive DRM proteins. DNMT3L recognizes chromatin and stimulates methyltransferase partners without supplying an independent DNA-methylation active site. The group also contains proteins catalogued as PWWP2B, underscoring that shared domains do not ensure conserved methyltransferase activity.

MPP-like and CASK-like MAGUK proteins assemble membrane-associated interaction complexes using conserved PDZ, SH3 and guanylate-kinase-like modules. Fly Metro stabilizes a perisynaptic complex with Dlg and DLin-7 through L27-domain interactions. The guanylate-kinase-like domain is an interaction module and does not establish GMP phosphorylation.

Auxilin-related proteins couple recognition of membrane-associated assemblies to Hsp70 chaperone recruitment. GAK adds a kinase domain, while auxilin contains a phosphatase-like region with a noncatalytic binding role.

Olfactomedin-domain proteins include OLFML2A/2B, noelins, myocilin and gliomedin. Extracellular and membrane-associated architectures occur, with distinct ligand interactions, tissue distributions and matrix or signaling roles.

The TGN38-related grouping includes the divergent fly regeneration protein Regeneration (Rgn). Fly rgn genetics supports a role in the formation of a proliferative regeneration blastema, while the relationship between that function and the intracellular trafficking mechanism associated with TGN38 remains unresolved.

Family of RING-finger peroxins centred on PEX10 orthologs: integral peroxisomal membrane proteins with an N-terminal membrane region (five transmembrane segments in the structurally characterized fungal complex) and a C-terminal cytosolically exposed C3HC4 RING finger. PEX10 is a subunit of the heterotrimeric PEX2-PEX10-PEX12 E3 ubiquitin ligase complex of the peroxisomal membrane, which doubles as the retrotranslocation channel for the PTS1 receptor PEX5. PEX10's RING (RF10) forms an extensive RING-RING interface with RF12; complex formation with PEX12 dramatically augments PEX10's E3 activity, which monoubiquitinates PEX5 for receptor recycling and, with RF12, polyubiquitinates stalled receptors for proteasomal turnover (RADAR quality-control pathway). Loss of function abolishes peroxisomal matrix protein import while leaving membrane assembly largely intact; biallelic human PEX10 mutations cause Zellweger spectrum disorders (complementation group 7). The main subfamily SF0 contains PEX10 orthologs across animals, fungi, amoebozoa and plants. Notably, the family also contains a fungal PEX2-ortholog subfamily (SF4: e.g. Komagataella PEX2, Podospora PEX2, Thermothelomyces PEX2) - a different subunit of the same ligase complex - so PANTHER splits PEX2 orthologs between this family and PTHR48178. Both subunits share domain architecture, localization, complex membership and pathway, but their RING domains play mechanistically distinct roles (RF2 monoubiquitinates the receptor's N-terminal cysteine; RF10/RF12 cooperate in lysine polyubiquitination).

This PANTHER group combines NIP7 ribosome-biogenesis proteins with cyclin-dependent kinase regulatory subunits. NIP7 supports large-subunit pre-rRNA processing, whereas CKS proteins regulate kinase-associated cell-cycle machinery. These roles are biologically distinct despite their grouping under one family identifier.

This membrane-protein group includes OST-alpha transporters, TMEM184 proteins and fungal Hfl1. Characterized mammalian OST-alpha works with OST-beta in organic-solute transport, while Hfl1 recruits Atg8 during vacuolar membrane-protein turnover. A membrane-transport name therefore does not specify a conserved substrate or even the same cellular mechanism for every member.

Family of collagenous C-type lectins (collectins): secreted proteins that combine a collagen-like region with a Ca2+-dependent C-type carbohydrate-recognition domain and oligomerize into multivalent pattern-recognition molecules of innate immunity. The family name is dominated by one member (SP-A); the family in fact splits into two functionally distinct branches. The serum/complement branch - mannose-binding lectin (human MBL2, rodent Mbl1/Mbl2) and collectin-10/11 (CL-L1/CL-K1) - recognizes microbial carbohydrate patterns and activates the lectin pathway of complement through associated MASP serine proteases. The pulmonary surfactant branch - SP-A and SP-D - acts in the alveolar lining, where it contributes to surfactant homeostasis and largely complement-independent opsonization and immune modulation. Shared, family-wide biology: secretion, Ca2+-dependent carbohydrate binding, pattern-recognition activity, and enhancement of phagocytosis of bound microbes. Branch-specific biology (lectin-pathway complement activation; surfactant homeostasis and its multivesicular-body/lamellar-body trafficking compartment) does not propagate safely across the family, and both directions of leakage have occurred in past PAINT-derived IBAs on human MBL2.

MAPK-related proteins include classical ERK, JNK, p38/Hog1 and plant MAPKs alongside other CMGC branches such as NLK-related kinases. They share phosphorylation chemistry but differ in activation systems and substrates.

CDKs and CDK-like kinases regulate cell-cycle events, transcription and other processes through protein phosphorylation. Cyclin or other activator requirements and substrate repertoires differ among paralogs.

This group links class-C receptor proteins whose extracellular ligand-recognition regions support distinct sensory functions. Calcium-sensing, glutamate-responsive and vomeronasal receptors cannot be assigned each other's ligands from shared receptor architecture. For mouse Vmn2r73, receptor-family placement is a starting point for investigating vomeronasal signaling, not proof of a particular pheromone or peptide ligand.

The E2 fold includes enzymes for ubiquitin, SUMO, NEDD8 and ISG15 conjugation as well as noncatalytic E2-like regulators. Catalytic thiol chemistry and modifier recognition must both be considered when transferring enzyme functions.

This family collects UBC-fold E2 enzymes. Most members are genuine ubiquitin-conjugating enzymes: they accept ubiquitin from E1 onto an invariant catalytic cysteine, forming an E2~ubiquitin thioester, and hand it to substrates in cooperation with E3 ligases, which supply most of the substrate and linkage specificity. The family is broader than that core in two directions that matter for annotation. First, it contains catalytically dead UEV proteins (UBE2V1/UBE2V2, yeast Mms2, worm uev-1) that keep the UBC fold but have no catalytic cysteine; they act as obligate partners of UBE2N/Ubc13 in K63 chain synthesis rather than as conjugating enzymes themselves. Second, in the tree version behind the cached PAINT slice it contains the NEDD8-conjugating branch (UBC12/UBE2M and UBE2F), which retains the catalytic cysteine but charges NEDD8, not ubiquitin. Linkage specificity is unevenly distributed across the active members: UBE2K, UBE2N-UBE2V and UBE2S build defined K48, K63 and K11 chains respectively, while the UBE2D (UbcH5) and UBE2E groups are promiscuous E2s whose linkage output in vitro spans many ubiquitin lysines and in vivo is set by the partner E3. That unevenness is the root of the family's over-annotation pattern: linkage-specific process terms seeded from promiscuous members.

Rho-family proteins share a small-GTPase fold and regulate cellular organization through nucleotide-dependent interactions. Their catalytic and regulatory properties vary among conventional and atypical branches.

NR5-family nuclear receptors are DNA-binding transcriptional regulators that include vertebrate steroidogenic and metabolic regulators and insect FTZ-F1 proteins. They share nuclear-receptor domain architecture while controlling lineage-specific developmental and physiological programs.

The PANTHER family carries a Caskin name, but the benchmark member is a maize sequence. A cross-kingdom match needs architectural verification before the functions of animal neuronal scaffolds can be assigned to the plant protein.

Ankyrin-repeat proteins form a broad interaction-module grouping spanning cytoskeletal ankyrins, kinase-containing signaling proteins, ubiquitin-system adaptors and toxins. The repeats provide protein-contact surfaces; the surrounding domains determine the biological mechanism.

ABCB-related transporters combine ATP-binding domains with membrane-spanning regions to move chemically diverse substrates. Members occur in different membranes and include bacterial exporters and eukaryotic organellar and cellular transport systems.

This rhodopsin-like receptor family contains membrane receptors that couple ligand recognition to cellular signaling. The GHSR branch recognizes ghrelin and growth-hormone secretagogues and regulates endocrine and feeding responses.

Chymotrypsin-related proteins include active serine proteases and noncatalytic protease-fold proteins. Drosophila Scarface is a secreted regulator of epithelial morphogenesis and laminin organization that lacks the canonical protease catalytic triad. Its retained fold does not establish endopeptidase activity.

CUB domains occur in extracellular recognition proteins, cubilin, procollagen-processing factors, metalloproteases and membrane receptors. A common extracellular interaction module is distinct from the activity of additional catalytic domains or a reproductive role.

This insect protease-related family contains proteins with serine-protease-like domains and variable additional architecture. Catalytic enzymes and noncatalytic protease homologues can participate in immune or developmental systems through different mechanisms.

Homeobox proteins share a compact DNA-recognition domain and have diversified into regulators of many cellular and developmental programs. Fungal members include transcriptional regulators with functions that differ from animal developmental homeobox proteins.

PTHR24351 is a large clade of AGC-group protein serine/threonine kinases named after the ribosomal protein S6 kinases but spanning much more than S6K. Its members include the p70/p85 S6 kinases (S6K1/2), the p90 ribosomal S6 kinases (RSK1-4), the mitogen- and stress-activated kinases (MSK1/2), the Akt/PKB kinases, SGK kinases, and fungal/protist relatives such as budding-yeast Sch9 and fission- yeast psk1. All are ATP-dependent protein serine/threonine kinases that carry the canonical bilobal protein-kinase fold followed by an AGC-kinase C-terminal extension, and are activated downstream of growth-factor and nutrient signalling (PI3K/PDK1/mTOR and RAS/ERK inputs). They phosphorylate serine/threonine residues on cytoplasmic and nuclear substrates to control translation, cell growth, survival, and transcription. The catalytic machinery (glycine-rich loop, the VAIK beta-3 lysine that positions ATP, the HRD catalytic aspartate, and the DFG magnesium-binding aspartate) is conserved across the family; what varies between subfamilies is upstream activation, substrate specificity, and downstream pathway role, not the core kinase chemistry.

A very large family (14,981 proteins, 149 subfamilies, 4,302 taxa in the cached InterPro/PANTHER metadata) of Krueppel-type tandem C2H2 zinc-finger proteins. Members are built from arrays of C2H2 fingers, each coordinating one zinc ion through two cysteines and two histidines and contributing base-specific major-groove contacts, so the shared, architecture-determined function of the family is nuclear sequence-specific DNA binding in the service of RNA polymerase II transcription regulation. What varies between members is everything above that generic level: the DNA target sequence (dictated by the specificity residues of each finger array, which diverge rapidly under lineage-specific duplication), the regulatory direction (the family holds experimentally verified activators such as human ZNF300 and repressors such as human ZNF140 side by side, sometimes as seeds of the same PAINT node), the effector modules present (KRAB and SCAN domains in many members, none at all in others, including the Xenopus oocyte/gastrula XlCOF-type members), and in at least one branch the DNA target class itself (the ZNF445 clade binds methylated imprinting-control regions rather than ordinary cis-regulatory elements). PAINT annotates this family at many separate internal nodes with deliberately generic terms (nucleus; DNA-binding transcription factor activity, RNA polymerase II-specific; RNA polymerase II cis-regulatory region sequence-specific DNA binding; regulation of transcription by RNA polymerase II), reserving directional child terms (GO:0001227/GO:0001228) for narrower clades, and in one place uses an IRD to negate an inherited binding term - evidence of active, branch-aware curation rather than blanket propagation.

This kinase-related family contains signaling proteins with differing catalytic competence and regulatory roles. The IRAK3 branch regulates signaling downstream of IL-1 and Toll-like receptors and has a noncanonical kinase active-site configuration.

Sen15 proteins are structural components of eukaryotic tRNA-splicing endonuclease complexes. They support the assembly and function of a complex whose catalytic subunits cleave intron-containing precursor tRNAs.

These bacterial extracytoplasmic-function sigma factors direct promoter recognition by RNA polymerase during transcription initiation. Their promoter targets and inducing conditions vary among lineages.

TMEM268-family proteins contain a conserved DUF4481-associated membrane-protein architecture. In human gastric cancer cells, TMEM268 binds integrin beta4 and helps maintain integrin-associated adhesion machinery; its conserved biochemical activity and the corresponding role of fly CG18507 are unresolved.

Metazoan family of long, dimeric coiled-coil proteins that act as cargo adaptors and activators of cytoplasmic dynein-1. Members share a three-segment coiled-coil architecture. The N-terminal coiled coil (CC1, with the CC1 box) binds the dynein light intermediate chain and the dynein tail. It also runs along the dynactin Arp1 filament, so dynein, dynactin and BICD form a stable, highly processive minus-end-directed motor complex. The C-terminal coiled coil (CC3) selects cargo and, in the cargo-free state, folds back to autoinhibit motor binding. Vertebrates have two paralogs, BICD1 (SF3) and BICD2 (SF7); invertebrates have a single BicD (SF6, Drosophila BicD and C. elegans BICD-1). Cargoes are lineage- and context-specific. Vertebrate BICD2 binds RAB6-GTP on Golgi-derived vesicles (Golgi-to-ER retrograde and secretory transport). It also binds RANBP2 at nuclear pores in G2 and nesprin-2 at the nuclear envelope of migrating neurons, and these nuclear-envelope cargoes drive nuclear migration. Drosophila BicD transports Egalitarian-bound mRNAs into and within the oocyte, and Rab6-positive membranes and clathrin. It is also needed for nuclear migration in photoreceptor precursors and neurons. The adaptor and motor-activator function (dynein and dynactin binding, cargo-licensed dynein activation) is conserved across the family. Cargo-specific processes are not. The BICD-related proteins BICDR1/BICDL1, BICDL2 and Drosophila BicDR are in a separate PANTHER family (PTHR32123), not this one.

BURP-domain proteins in this group include polygalacturonase-associated noncatalytic subunits and related plant proteins. A BURP domain does not itself establish glycoside hydrolase activity or a conserved reproductive phenotype.

This grouping contains animal FMC1-related proteins with a proposed relationship to mitochondrial ATP synthase assembly factors. Yeast Fmc1 is a soluble mitochondrial-matrix protein that helps F1 assembly under heat stress; equivalent activity of the fly CG34117 family branch is not directly established.

TTC39/IML2-related proteins include metazoan TTC39 paralogs and fungal proteins associated with inclusion-body handling. Repeat-mediated interactions support distinct cellular functions in different branches.

Patatin-like proteins include plant lipid hydrolases and bacterial phospholipase effectors. Intact catalytic domains support lipid ester hydrolysis, whereas truncated or inactive members retain family resemblance without the reaction. The current PANTHER vocabulary label 'xylose isomerase' does not describe the retrieved members.

Reverse-transcriptase domains occur in different mobile-element and viral architectures. The retrieved reviewed entries emphasize hepadnaviral polymerases, which do not establish the life cycle or integration mechanism of a metazoan repeat-associated sequence.

MarR-related helix-turn-helix regulators recognize distinct promoters and respond to different ligands or redox states. The group includes antibiotic-response regulators and many regulators of other physiological systems.

Calcyphosin and calcyphosin-like proteins are EF-hand proteins with a calcium-sensing architecture. Human calcyphosin binds calcium in four EF-hand motifs and is largely monomeric; the related CAPSL branch retains calcium-binding-associated sequence signatures. Their specific cellular partners and conserved physiological outputs are incompletely characterized.

The family includes amino-acid-binding proteins and solute-binding modules associated with lytic transglycosylases. Binding-domain conservation does not establish either a membrane pore or the enzymatic activity of a fused domain.

NtR belongs to an insect branch of the Cys-loop ligand-gated ion-channel superfamily. The neuronal-channel ligand-binding architecture and C-terminal membrane region support a channel-subunit role, while its gating ligand and ion selectivity remain unidentified.

Glucuronokinases use ATP to phosphorylate glucuronic acid in a route for recycling uronic acids into nucleotide-sugar metabolism. They have GHMP-kinase architecture rather than the reaction implied by a uridyl-pyrophosphorylase name.

Fungal Yap/AP-1-related bZIP transcription factors regulate stress-responsive gene expression. Their shared DNA-binding and dimerization architecture is used in distinct oxidative, chemical and metabolic response programs.

This AKR-related group contains experimentally named sugar and pyridoxal dehydrogenases with divergent substrate preferences. The conserved barrel and nucleotide-binding architecture support oxidoreductase chemistry, while substrate-recognition loops distinguish individual reactions. A broad aldo-keto-reductase superfamily description does not determine the physiological direction or substrate of each member.

Subtilisin/kexin-related serine proteases process protein precursors in diverse organisms. Animal proprotein convertases include enzymes that mature peptide hormones; fungal and bacterial members act in other proteolytic settings. Substrate recognition, maturation and trafficking distinguish their biological roles.

The **beta subunit** counterpart to PTHR43380: this family holds the E1-beta chains that pair with a 2-oxoisovalerate dehydrogenase alpha subunit to build the alpha2-beta2 E1 decarboxylase of the branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex. Every reviewed member in the fetched slice is a branched-chain E1-beta: human, bovine, rat and mouse BCKDHB, Dictyostelium bkdB, the thermophilic fungus Thermochaetoides CTHT_0041430, Arabidopsis BCDH BETA1 and DIN4, Pseudomonas putida and P. aeruginosa bkdA2, and Mycobacterium tuberculosis bkdB. The family therefore spans bacteria, fungi, plants, amoebozoa and animals, which is consistent with BCAA catabolism being an ancient and broadly conserved pathway. Mechanistically the beta subunit does not have an active site of its own: the two E1 active sites lie at the alpha/beta' interfaces, and the beta chain supplies the thiazolium-ring contacts of the shared thiamine diphosphate cofactor (UniProt P21953 BINDING 152, "ligand shared with alpha subunit"), several structural K+ sites, and the surfaces that hold the heterotetramer together and dock it onto the E2 (DBT) core. Consequently every well-founded molecular-function annotation on a member of this family is either a cofactor/ion-binding term that the subunit does enable on its own, or the complex-level branched-chain 2-oxo acid dehydrogenase activity with a contributes_to qualifier. Loss of the beta chain destabilises the alpha chain and collapses the whole complex, which is why human BCKDHB null alleles cause maple syrup urine disease type 1B.

This family collects the **alpha subunit** of the "type II", heterotetrameric (alpha2beta2) thiamine-diphosphate-dependent E1 components of 2-oxo acid dehydrogenase multienzyme complexes. Every member is one half of an alpha2-beta2 decarboxylase whose two active sites sit at the alpha/beta' interfaces, with the ThDP cofactor shared between the subunits: the alpha subunit supplies the diphosphate- and Mg2+-binding residues, the beta subunit (a separate PANTHER family, PTHR42980 for the branched-chain type) supplies the thiazolium-ring contacts. All members catalyse the same two half-reactions - ThDP-dependent decarboxylation of a 2-oxo acid, then reductive acylation of the lipoyl-lysine of the E2 core. What differs between members is the **substrate** and therefore the complex they belong to. The core group acts on the branched-chain 2-oxo acids derived from leucine, isoleucine and valine (human/bovine/rat/mouse BCKDHA, C. elegans bckd-1A, Dictyostelium bkdA, Arabidopsis At1g21400 and At5g09300, bacterial bkdA1/bfmBAA/bkdA), forming the E1 component of the branched-chain alpha-ketoacid dehydrogenase complex and running the committed, rate-limiting step of BCAA catabolism. A second group acts on pyruvate, forming the E1 component of the pyruvate dehydrogenase complex and feeding acetyl-CoA into the TCA cycle. The chemistry is shared; the substrate specificity, the complex, and the pathway are not. Whether that second group really sits inside this family is where the cached sources disagree, and the disagreement matters enough to state plainly. The **PAINT book for PTHR43380** contains a pyruvate clade: node PTN008519424 carries GO:0004739 and GO:0006086, seeded entirely by pyruvate dehydrogenase E1-alpha genes. The fetched **InterPro slice** likewise lists fourteen bacterial pdhA proteins under PTHR43380:SF1. But PANTHER's own HMM **member index** (interpro/panther/panther-members.tsv) places the pdhA/PDHA proteins it has entries for in a different family entirely - P21881 (Bacillus subtilis pdhA) in PTHR11516:SF41 and P08559 (human PDHA1) in PTHR11516:SF52 - while confirming P12694 and P11178 in PTHR43380:SF1 and Q84JL2 in PTHR43380:SF11. The likeliest reading is that the sources are pinned to different PANTHER releases. Nothing here resolves it, so this review treats the PAINT book as authoritative for IBA questions (it is what actually propagates) and flags the classification conflict rather than picking a winner.

DPM1-related glycosyltransferases transfer mannose from nucleotide-sugar donors to lipid-linked acceptors. Eukaryotic dolichol-phosphate mannose synthases differ in membrane-anchoring and subunit organization, while related microbial proteins supply other lipid-linked mannose donors.

Homologous subunits of respiratory complex I and chloroplast NDH: NuoM / mitochondrial ND4 / plastid NdhD. Respiratory complexes receive electrons from NADH, whereas the chloroplast NDH complex lacks the NADH-oxidizing module and uses reduced ferredoxin to reduce plastoquinone. Coupled proton translocation is conserved. The chloroplast complex contributes to cyclic photosynthetic ATP production and has evidence for chlororespiratory participation; chloroplast localization does not by itself negate respiratory process terms.

LepA/GUF1 proteins act with bacterial or organellar ribosomes in translation. Mitochondrial, chloroplast and bacterial forms share translation-factor architecture but differ in targeting and translation system.

This aldehyde-dehydrogenase family contains ALDH7/aminoadipate-semialdehyde and ALDH4/pyrroline-5-carboxylate dehydrogenase branches. These enzymes share a dehydrogenase framework while acting on different semialdehydes in amino-acid metabolism; individual members also contribute to protection from reactive aldehydes.

FtsH-related proteins combine AAA-type ATPase machinery with a protease-related region and occur in membrane-associated protein-handling systems. The chloroplast import machinery illustrates diversification of these components beyond a simple assignment of protein degradation.

This family includes aconitate-delta-isomerases and enzymes assigned to methylitaconate and oxalomesaconate interconversion. A shared enzyme fold does not identify the substrate or physiological pathway.

Crotonase-fold proteins catalyze chemically distinct reactions on acyl-CoA and non-CoA substrates. This grouping includes enoyl-CoA-hydratase-related proteins and a characterized 6-oxocamphor hydrolase that cleaves a carbon-carbon bond. Active-site geometry and substrate recognition determine the reaction more precisely than the common fold.

Acyl-CoA-dehydrogenase-fold relatives perform diverse reactions, including fatty-acyl dehydrogenation and specialized oxidative or desulfinating chemistry. ACAD9 is additionally recruited to mitochondrial complex-I assembly; ECSIT binding releases its FAD and suppresses dehydrogenase activity in the assembly state. This state-dependent switch differs from constitutive catalytic inactivity.

WD40-repeat family whose best-characterized members are the LIS1 orthologs: human PAFAH1B1/LIS1, Drosophila Lis-1, C. elegans LIS-1, Aspergillus nidulans NudF and budding yeast Pac1. LIS1 is an N-terminal LisH/coiled-coil dimerization domain followed by a seven-bladed WD40 beta-propeller. The propeller binds the AAA+ motor domain of cytoplasmic dynein heavy chain, where the ring meets the stalk, and regulates dynein mechanochemistry. It holds dynein in a persistent high-force, microtubule-bound state and relieves dynein autoinhibition, promoting assembly of activated dynein-dynactin-adaptor complexes and targeting dynein to microtubule plus ends. LIS1 works with the NudE/NudEL coiled-coil proteins (PTHR10921). The conserved biological outputs are dynein-driven nuclear migration (fungal hyphal nuclear distribution, yeast spindle movement into the bud, C. elegans pronuclear migration, nucleokinesis in migrating neurons) and retrograde transport. Metazoan LIS1 also acts at kinetochores, centrosomes and the nuclear envelope in mitosis, and human haploinsufficiency causes classical lissencephaly. Vertebrate LIS1 has a second, lineage-specific role as the non-catalytic regulatory (beta) subunit of cytosolic PAF acetylhydrolase Ib. Fly Lis1 cannot bind the fly alpha-subunit homolog. In the PANTHER 19 tree the family also contains WD40 proteins that are not LIS1 orthologs: the mammalian leaves named FBXW11 (SF4), nematode wdr-5.2/wdr-5.3 (SF17), and the fungal AFUA_1G12380 group (SF3). SF13 itself also holds S. pombe pop1 (the family's namesake SCF F-box protein), Candida albicans CDC4 and Dictyostelium agtA alongside the invertebrate and fungal LIS1 orthologs.

DNAJC3/P58IPK-related proteins combine repeat-mediated protein interactions with a J-domain cochaperone module. Their protein-folding roles are coupled to cellular stress responses and the chaperone systems present in their compartment.

This broad sequence-classifier group includes CHK2/Cds1, CDC7, viral and microbial kinases, and probable inactive kinase-like proteins. Shared kinase architecture does not unify the regulated biological processes. A0BFB4 retains a verified PTHR44167:SF18 sequence classification, while its actual PAINT tree places it in the distinct UNC-51-related family PTHR24348 below an autophagy-bearing ancestor; these resources require reconciliation.

DCXR-related short-chain dehydrogenases/reductases reduce small carbonyl substrates, including L-xylulose and alpha-dicarbonyls in characterized mammalian members. The common SDR catalytic framework does not establish the ACP-bound fatty-acid substrate of FabG.

Methyltransferase type-11 proteins including fission-yeast SPAC25B8.09 and budding-yeast Tmt1. Tmt1 catalyzes trans-aconitate methylation and also modifies 3-isopropylmalate, its major endogenous substrate in yeast extracts. PomBase transfers trans-aconitate activity to SPAC25B8.09 by curated orthology, while its predominant physiological substrate remains unresolved.

This sequence-classification family includes the PTK7 receptor pseudokinase branch. PTK7 preserves an intracellular kinase fold but has a structurally occluded ATP pocket; it organizes partner-mediated signaling at cell contacts. Related fly Off-track developmental functions cannot be projected wholesale into vertebrate anatomy.

The family includes plant ADMETOS-related proteins with a J domain. A J domain provides a potential chaperone-interaction module, but full-protein targeting and specialized biological functions require additional evidence.

Mitochondrial carrier-related proteins use a repeated membrane-transport architecture to exchange diverse metabolites. Substrate specificity and physiological coupling differ among carrier branches.

The family includes ATP-dependent group I chaperonins such as Hsp60/GroEL and the divergent mitochondrial chaperone Tcm62. These proteins assist protein biogenesis, but their folding mechanisms and dependence on ATP are not uniform.

Hsp70-related chaperones share nucleotide-binding and substrate-interaction architecture but differ in compartment and dominant chaperone-system role. Hsp110-related proteins provide an important boundary within this broader structural group.

Class-III PLP-enzyme relatives catalyze several distinct reactions. AGXT2 is a transaminase, ETNPPL degrades phosphoethanolamine and PHYKPL degrades phosphohydroxylysine; other classified proteins have decarboxylase or racemase functions. Absence of transaminase activity in a relative does not establish a catalytically inactive protein.

The retrieved group includes RGLG RING-type ubiquitin ligases and proteins carrying copine-related names. Ligase activity depends on the RING-containing architecture and its E2 partner; membrane association and substrate choice differ among paralogs.

This zinc-transporter group includes fungal Cis4/Msc2, animal ZNT5/ZNT7 and related plant proteins. Members connect secretory-pathway metal supply with zinc homeostasis and the maturation of zinc-dependent cellular functions.

Family of large multi-PLAT-repeat (lipoxygenase homology / LH2 domain) proteins, integrated as InterPro IPR052970 ("Inner ear hair cell lipoxygenase homology domain-containing protein"). The only experimentally characterized clade is the amniote LOXHD1 subfamily (PTHR45901:SF3): mouse and human LOXHD1 are nonenzymatic stereociliary proteins of cochlear hair cells, localized along the stereociliary membrane and enriched at the tips of the shorter (row 2/3) stereocilia, where LOXHD1 is required to maintain the TMC1 mechanotransduction channel near the lower tip-link insertion and to preserve mature mechanotransduction currents. Biallelic human LOXHD1 variants cause DFNB77 progressive autosomal-recessive nonsyndromic hearing loss; mouse mutants lose inner-hair-cell mechanotransduction currents after the first postnatal week. Despite the "lipoxygenase homology" name, no catalytic activity, substrate or reaction has been demonstrated for any member. PANTHER's official family name derives from an uncharacterized Caenorhabditis briggsae protein (CBG12474), reflecting a broad family (4074 proteins, ~3327 taxa, 3 subfamilies in InterPro) in which most members - including the nematode-type members - are functionally uncharacterized, so hearing- and stereocilium-specific terms cannot be extended beyond the vertebrate LOXHD1 clade.

IA-2/PTPRN-related proteins are secretory-vesicle membrane proteins with phosphatase-like intracellular domains. Their conserved roles concern vesicle abundance and secretion, with catalytic claims requiring attention to substrate and assay conditions.

VTC-related proteins participate in fungal vacuolar polyphosphate systems. The complex combines polyphosphate synthesis, membrane translocation and regulatory inputs through distinct subunit roles.

Double-stranded-RNA-binding cofactors regulate small-RNA processing and loading by cooperating with RNA-silencing enzymes. Different proteins and isoforms recruit or tune distinct processing pathways.

Gemin5-related proteins recognize RNA and contribute to ribonucleoprotein assembly. Mammalian Gemin5 delivers snRNAs to the SMN assembly machinery and also has RNA- and translation-associated functions outside a single assembly step.

FBXO42 proteins are F-box substrate-recognition components of SCF ubiquitin-ligase complexes. In fly oocytes, Fbxo42 controls PP2A-B56 abundance and supports synaptonemal-complex maintenance; substrate choice varies among organismal contexts.

Wss1-related metalloproteases act in the resolution of DNA-associated protein obstacles, including DNA-protein crosslinks. DNA association and recruitment mechanisms couple proteolysis to genome-maintenance pathways.

FOXN-related transcription factors share a forkhead DNA-binding domain but regulate distinct developmental programs. The family includes vertebrate FOXN regulators and related invertebrate proteins such as fly Jumu.

Ulp2/SENP-related proteases regulate SUMO modification by processing SUMO conjugates and chains. Their catalytic framework is coupled to different cellular substrates and localization mechanisms across lineages.

BIN3/Rvs-related BAR-domain proteins couple membrane organization to cytoskeletal and cellular processes. Related fungal proteins differ in their contributions to endocytosis, actin organization and stress responses.

TBC-domain proteins include Rab GTPase-activating enzymes and noncatalytic trafficking regulators. Rab preference, organelle recruitment and catalytic competence vary among branches.

MAP kinase kinases phosphorylate downstream MAP kinases as components of conserved signaling cascades. Different branches specify different kinase partners and connect the conserved catalytic step to distinct cellular responses.

These plant proteins contain C2H2-type zinc-finger domains. The retrieved characterized-member set is sparse, so specific transcriptional targets, signaling roles and localization boundaries remain incompletely resolved.

The Arabidopsis member AT4G38370 is associated with a phosphoglycerate-mutase-related enzyme fold. Its physiological substrate and the functional uniformity of its PANTHER family are unresolved from the available target evidence.

The retrieved family includes plant receptor-like proteins RLP19 and PII-2. Extracellular leucine-rich repeats provide a recognition surface; receptor-associated signaling can occur without an intrinsic protein kinase domain.

This major-facilitator-superfamily group contains membrane proteins associated with sugar and related-solute handling. Transported substrates, affinity and coupling mechanisms differ among branches.

These glycosyltransferases act on diverse plant metabolites, with variation in sugar donor, acceptor and modified position. The retrieved family includes enzymes for flavonoids, terpenoids and other specialized metabolites.

This sparse grouping contains the divergent fly uL1-like protein CG13096 and varicella-zoster-virus UL47/ORF11 tegument proteins. The shared L1-like domain suggests an RNA-contact architecture, but does not establish a common ribosomal, viral or transport mechanism across these proteins.

Death-effector-domain-associated regulatory proteins organize signaling interactions rather than sharing one universal enzymatic reaction. PEA15 regulates kinase localization and signaling outputs through protein interactions.

Family of PEX2 orthologs: integral peroxisomal membrane proteins with an N-terminal membrane region (five transmembrane segments in the structurally characterized fungal complex) and a C-terminal cytosolically exposed RING-HC zinc finger. Across eukaryotes, PEX2 assembles with the other two RING peroxins, PEX10 and PEX12, into a heterotrimeric E3 ubiquitin ligase complex in the peroxisomal membrane that doubles as a retrotranslocation channel for the PTS1 import receptor PEX5: the PEX2 RING (RF2) sits above the channel pore and monoubiquitinates the receptor's N-terminal cysteine to license ATP-dependent extraction by PEX1-PEX6, sustaining peroxisomal matrix protein import. The fetched member slice is uniformly PEX2 orthologs (subfamily SF1) from animals, fungi, amoebozoa, and plants, and loss of function in any of them disrupts peroxisome biogenesis (human PEX2 mutations cause Zellweger spectrum disorders, complementation group 10). Mammalian PEX2 has additional lineage-restricted roles as the E3 driving starvation-induced pexophagy and as a ROS-stabilized ligase that polyubiquitinates the lipase ATGL to downregulate lipolysis; these are not demonstrated outside mammals. Note the family boundary quirk: some fungal PEX2 orthologs (e.g. Komagataella PEX2, Thermothelomyces PEX2) are classified not here but as subfamily SF4 of the PEX10 family PTHR23350, so PTHR48178 does not contain all PEX2 orthologs.

EXT-related glycosyltransferases contribute to extracellular polysaccharide biosynthesis. The broader family includes animal heparan-sulfate enzymes and plant glycosyltransferases associated with different cell-wall glycans.

Secreted class-II cytokines of the IL-10 group: compact, mostly amphipathic six-helix-bundle proteins (IL-10 itself is an intertwined domain-swapped homodimer) that signal through pairs of class-II cytokine receptor chains and converge on JAK/TYK2-driven STAT3 phosphorylation. All members are secreted and all are cytokines, so secretion, cytokine activity, participation in immune responses and positive regulation of JAK-STAT signalling are true throughout. What is *not* shared is the receptor used and, critically, the direction of the immunological effect. IL-10 (SF5) acts on haematopoietic cells through IL-10RA/IL-10RB and is the prototypical anti-inflammatory cytokine, suppressing pro-inflammatory cytokine production and MHC class II expression. IL-19, IL-20 and IL-24 (SF3, SF2, SF4) act mainly on epithelium through IL-20 receptor complexes (IL-20RA/IL-20RB, with IL-22RA1/IL-20RB additionally used by IL-20), and IL-26 (SF1) acts on epithelium through IL-20RA/IL-10RB; these members are associated with epithelial defence, keratinocyte and mucosal responses and are frequently pro-inflammatory. The IL-10 subfamily (SF5) also contains virally captured homologs (Epstein-Barr virus BCRF1, human cytomegalovirus UL111A, equine herpesvirus 2 E7), which retain IL-10-like immunosuppressive activity but exercise it as host-immune-evasion factors rather than as part of a host immune response. Note that IL-22, often discussed alongside these cytokines, is *not* a member of this PANTHER family. The InterPro slice records 2786 proteins across 2506 taxa (integrated entry IPR020443); the fetched entries.csv covers the 43 reviewed (UniProtKB/Swiss-Prot) members, which are all vertebrate or herpesviral.

Chalcone-flavanone isomerase (CHI), the catalytic family of the chalcone-isomerase clan.

Stage II sporulation protein E (SpoIIE), the sporulation-specific PP2C-family phosphatase.

Alpha-subunit TIM-barrel domain of D-lysine 5,6-aminomutase (adenosylcobalamin-dependent).

PQQ/WD40-like beta-propeller repeat domain; named for BamB but a fold shared across functions.

Short-chain dehydrogenase/reductase (SDR) domain; named for enoyl-ACP reductase but generic SDR.

Uracil-phosphoribosyltransferase-like domain; eponymously Upp, but also found in uridine kinases.

NDP-sugar-modifying extended-SDR domain; named for GDP-mannose 4,6-dehydratase but broader.

Alpha subunit of D-ornithine 4,5-aminomutase (adenosylcobalamin-dependent).

Small (LeuD) subunit of 3-isopropylmalate dehydratase (isopropylmalate isomerase).