CLN5 is a glycosylated lysosomal lipid enzyme that promotes bis(monoacylglycero)phosphate (BMP) formation and has cysteine-dependent palmitoyl-thioester hydrolase activity. Its endogenous thioester substrates remain unidentified, and its contribution to cellular BMP pools depends on the extracellular lipid environment and other lysosomal enzymes. CLN5 passes through the secretory pathway as a processed precursor and occupies the lysosomal lumen and luminal membrane surface. Cellular studies connect it to Rab7 activation and retromer-dependent recycling of lysosomal sorting receptors. Loss of CLN5 causes a neuronal ceroid lipofuscinosis with progressive neurodegeneration.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:12134079 Neuronal ceroid lipofuscinoses are connected at molecular le... | MODIFY | Summary: Specify the experimentally observed association with a protease. Reason: The original cell-free pull-down and cellular coimmunoprecipitation experiments support CLN5 association with TPP1/CLN2. The 2002 assay detects its precursor, whereas an independent mouse CLN5 pull-down preferentially captures mature TPP1. GO:0002020 specifies the authenticated protease partner class; it does not assert that CLN5 activates TPP1 or is itself a protease. Proposed replacements: protease binding |
| GO:0005515 protein binding | IPI PMID:12134079 Neuronal ceroid lipofuscinoses are connected at molecular le... | KEEP AS NON CORE | Summary: Retain the directly measured CLN3 interaction. Reason: The original study tests CLN5 and CLN3 by cellular coimmunoprecipitation and cell-free pull-down, with GST and unrelated-protein controls. Two exact IntAct records preserve the assay roles, tags and construct features. This is an interaction result, without a demonstrated autonomous adapter or transport activity. |
| GO:0005515 protein binding | IPI PMID:14699076 Two motifs target Batten disease protein CLN3 to lysosomes i... | KEEP AS NON CORE | Summary: Retain CLN3 binding independently of its targeting motifs. Reason: The original full text shows that CLN3 targeting-motif mutants retain CLN5 interaction in cotransfected COS-1 cells. The authors distinguish this association from CLN3 lysosomal targeting, which does not require the interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:22431521 The role of ceroid lipofuscinosis neuronal protein 5 (CLN5) ... | MODIFY | Summary: Specify association with the small GTPase RAB5A. Reason: Human-cell coimmunoprecipitation detects CLN5 association with Rab5 as well as Rab7, but not the Rab1 control. The verified partner class supports small GTPase binding; the assay does not establish purified direct contact, and CLN5 depletion did not reduce Rab5 GTP loading. Proposed replacements: small GTPase binding |
| GO:0005515 protein binding | IPI PMID:22431521 The role of ceroid lipofuscinosis neuronal protein 5 (CLN5) ... | MODIFY | Summary: Specify association with the small GTPase RAB7A. Reason: The original cellular assays detect CLN5 with wild-type, active and inactive Rab7 constructs. Small GTPase binding is a more informative description of this association, while the accompanying GTP-loading phenotype does not establish intrinsic exchange-factor or GAP chemistry. The bridge across the lysosomal membrane remains unresolved. Proposed replacements: small GTPase binding |
| GO:0005515 protein binding | IPI PMID:22431521 The role of ceroid lipofuscinosis neuronal protein 5 (CLN5) ... | KEEP AS NON CORE | Summary: Retain the experimentally supported sortilin association. Reason: Reciprocal cellular coimmunoprecipitation supports CLN5–sortilin association at the tested pH conditions, with CD63 and prosaposin comparisons. Sortilin depletion did not block CLN5 lysosomal targeting, so the positive association is not converted into a claim that CLN5 is sortilin cargo. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Specify binding to an IGF2-containing precursor construct. Reason: Three exact positive HuRI records support the P01344-3 pair, including a sufficient binding region of residues 57–236. Official isoform reconstruction maps this region to the canonical IGF2 precursor sequence, which contains the growth-factor region and its processing segments. The IGF-binding refinement describes the authenticated protein class at this assay scope; it does not demonstrate binding to isolated mature hormone or a native signaling role. Proposed replacements: insulin-like growth factor II binding |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the verified FDFT1 screen interaction. Reason: Three exact positive HuRI records identify the tagged squalene-synthase partner in array, prey-pooling and validated two-hybrid assays. The interaction is retained as non-core evidence without transferring the partner activity to CLN5 or inferring a physiological encounter from the screen alone. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the verified SLC41A1 screen interaction. Reason: Three exact positive HuRI records identify the tagged magnesium-transporter partner in array, prey-pooling and validated two-hybrid assays. The interaction is retained as non-core evidence without transferring the partner activity to CLN5 or inferring a physiological encounter from the screen alone. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Specify the observed association with phosphatase PLPP6. Reason: The three exact positive HuRI records identify Q8IY26, whose reviewed catalytic record establishes phosphatase activity. GO:0019902 describes this partner class without requiring an inhibitory or regulatory effect. This remains an assay-scoped binding refinement, not a new phosphatase activity for CLN5. Proposed replacements: phosphatase binding |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the verified GPR152 screen interaction. Reason: Three exact positive HuRI records identify the tagged putative receptor partner in array, prey-pooling and validated two-hybrid assays. The interaction is retained as non-core evidence without transferring the partner activity to CLN5 or inferring a physiological encounter from the screen alone. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the verified SLC41A2 screen interaction. Reason: Three exact positive HuRI records identify the partner fragment spanning residues 84–573 in array, prey-pooling and validated two-hybrid assays. The interaction is retained as non-core evidence without transferring the partner activity to CLN5 or inferring a physiological encounter from the screen alone. |
| GO:0005537 D-mannose binding | IDA PMID:16399764 Identification of sites of mannose 6-phosphorylation on lyso... | MARK AS OVER ANNOTATED | Summary: Mannose-bearing glycans do not establish mannose-binding activity. Reason: The original affinity-purification study positively identifies CLN5 among mannose-6-phosphorylated glycoproteins; the mannose-6-phosphate receptor is the binding reagent. Independently read CLN5 glycosylation experiments establish covalent N-glycans and trafficking effects. These observations support CLN5 as a glycan-bearing cargo rather than demonstrating the noncovalent mannose recognition required by GO:0005537. Original full-text access is incomplete, so this is a scoped interpretation of the authenticated assay and target table, not a claim of an untested-gene error. |
| GO:0005764 lysosome | EXP PMID:20052765 The neuronal ceroid lipofuscinosis protein CLN5: new insight... | ACCEPT | Summary: Retain lysosomal localization during CLN5 maturation. Reason: The authentic original abstract reports processing of human CLN5 into a mature lysosomal protein and MPR-independent targeting. The original author thesis supplies additional processing and localization context, while later directly read experiments corroborate lysosomal residence. No full original journal Methods access or current-product sequence mapping is claimed. |
| GO:0005764 lysosome | EXP PMID:24038957 Topology and membrane anchoring of the lysosomal storage dis... | ACCEPT | Summary: Retain the lysosomal compartment of processed CLN5. Reason: The original abstract distinguishes a type-II precursor from its cleaved luminal form and describes mature CLN5 association with lysosomal membranes. This positive localization is consistent with independently read microscopy and trafficking experiments; membrane attachment does not require a permanent transmembrane mature protein. |
| GO:0005764 lysosome | EXP PMID:24058541 The role of N-glycosylation in folding, trafficking, and fun... | ACCEPT | Summary: Retain the directly observed lysosomal localization. Reason: Wild-type tagged human CLN5 overlaps LAMP2 in HeLa cells and accumulates within enlarged Rab5A-Q79L endosomes. Glycosylation mutants retained in the ER or Golgi are separate observations and are not treated as normal CLN5 localization. Supporting Evidence: |
| GO:0005764 lysosome | EXP PMID:28442266 CLN5 is cleaved by members of the SPP/SPPL family to produce... | ACCEPT | Summary: Retain lysosomal localization of the SPPL3-released protein. Reason: The original abstract describes cleavage of a membrane-associated precursor to a soluble CLN5 fragment that reaches lysosomes. The historical 407-residue numbering and the released 93–407 fragment are source-specific; they are not relabeled as a current UniProt alternative product. Supporting Evidence: |
| GO:0005764 lysosome | IDA PMID:11971870 Lysosomal localization of the neuronal ceroid lipofuscinosis... | ACCEPT | Summary: Retain the original lysosomal localization result. Reason: The authentic abstract reports transiently expressed CLN5 in LAMP1-positive structures in BHK-21 cells. Secretion and glycosylation support a soluble secretory-pathway protein, and later full microscopy studies corroborate the lysosomal compartment. |
| GO:0005764 lysosome | IDA PMID:19941651 Novel interactions of CLN5 support molecular networking betw... | ACCEPT | Summary: Retain the wild-type human CLN5 lysosomal signal. Reason: The full study shows wild-type human CLN5 in lysosomes in HeLa cells, with separate mutant and partner-overexpression comparisons. Mouse CLN5 fusion-protein binding assays in the same paper are kept distinct from the human localization experiments. Supporting Evidence: |
| GO:0005764 lysosome | IDA PMID:22431521 The role of ceroid lipofuscinosis neuronal protein 5 (CLN5) ... | ACCEPT | Summary: Retain CLN5 localization in the endolysosomal system. Reason: The original full study follows CLN5 with lysosomal/endosomal markers and tests its association with sortilin and Rab proteins. Its localization persists after sortilin depletion; this supports the compartment without making sortilin an obligatory CLN5 cargo receptor. Supporting Evidence: |
| GO:0005764 lysosome | IDA PMID:37708259 The Batten disease gene product CLN5 is the lysosomal bis(mo... | ACCEPT | Summary: Retain the lysosomal site of the lipid-enzyme activity. Reason: The original authentic abstract places CLN5-mediated BMP synthesis in lysosomes, and independent human CLN5 microscopy establishes the compartment. The original full Methods remain inaccessible; no additional localization construct or stereochemical assay is inferred from that gap. |
| GO:0005764 lysosome | IEA GO_REF:0000120 | ACCEPT | Summary: Retain the combined lysosomal localization inference. Reason: The mouse ortholog, Ensembl product, CLN5-family domain and subcellular vocabulary converge on lysosomal localization. The exact mouse donor has experimental lysosomal/lumen evidence, and direct human localization independently corroborates the compartment. The original source components are preserved rather than counted as separate experiments. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q3UMW8 SUPPORTS TRANSFER Authenticated mouse Cln5 localization and direct human microscopy support the conserved location. Supporting Evidence: GO_REF:0000120 file:human/CLN5/CLN5-source-evidence.json |
| GO:0005765 lysosomal membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Retain functional association with the lysosomal membrane. Reason: The curated PAINT location is compatible with membrane-associated luminal CLN5 and its lipid-enzyme activity. The target is a legitimate experimentally grounded descendant source, not circular evidence. Historical ancestral placement was not independently reconstructed, and the term does not require a transmembrane mature CLN5 chain. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001809699 SUPPORTS TRANSFER The authenticated curated transfer and positive target membrane/localization evidence support retention; this is not a reconstruction of the historical tree. Supporting Evidence: GO_REF:0000033 file:human/CLN5/CLN5-source-evidence.json |
| GO:0005765 lysosomal membrane | IDA PMID:12134079 Neuronal ceroid lipofuscinoses are connected at molecular le... | ACCEPT | Summary: Retain the original lysosomal membrane-associated location. Reason: The original full study shows CLN5 colocalization with LAMP1 and membrane association of the longer precursor in its fractionation system. Later work distinguishes cleavage and luminal membrane association. Retain the compartment without treating all forms as integral membrane proteins. |
| GO:0005775 vacuolar lumen | IEA GO_REF:0000107 | MODIFY | Summary: Specify the lysosomal lumen within the broader vacuolar lumen. Reason: The exact mouse donor has an experimental vacuolar-lumen annotation and the original abstract describes soluble lysosomal Cln5. Human CLN5 occupies the lumen of enlarged endosomes en route to lysosomes and undergoes luminal processing. Lysosomal lumen is the informative target compartment, without changing the original orthology identifiers. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: UniProtKB:Q3UMW8 SUPPORTS TRANSFER Experimental donor and target luminal localization support refinement to the lysosomal compartment. Proposed replacements: lysosomal lumen Supporting Evidence: GO_REF:0000107 file:human/CLN5/CLN5-source-evidence.json |
| GO:0005783 endoplasmic reticulum | IDA PMID:12134079 Neuronal ceroid lipofuscinoses are connected at molecular le... | KEEP AS NON CORE | Summary: Retain the source-specific ER localization of precursor material. Reason: In the original COS-1 expression system, the N-terminal antibody produces reticular ER-like staining while the internal peptide antibody predominantly identifies lysosomal protein. This processing- and antibody-dependent observation is retained as non-core, distinct from disease-mutant ER retention and the main mature-protein location. |
| GO:0005794 Golgi apparatus | IDA PMID:12134079 Neuronal ceroid lipofuscinoses are connected at molecular le... | KEEP AS NON CORE | Summary: Retain the source-specific Golgi transit signal. Reason: The original N-terminal antibody overlaps the Golgi marker in cells expressing wild-type CLN5, whereas the internal peptide antibody mainly detects lysosomal protein. The Golgi signal is retained as trafficking/precursor context, without presenting Golgi retention of glycosylation mutants as the principal wild-type location. |
| GO:0005829 cytosol | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | Summary: Endosome-to-Golgi involvement does not establish residence in the cytosol. Reason: This electronic inference derives cytosol from the transport-process annotation. The underlying experiment measures recruitment of cytosolic retromer components, not a stable cytosolic location for mature CLN5. Secretory-pathway, luminal and membrane-associated CLN5 forms are directly supported; transient precursor fragments do not validate the inferred location of the mature protein. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: GO:0042147 SUPPORTS SOURCE BUT NOT TARGET A process-location implication conflates the compartment of retromer machinery with that of the CLN5 product. Supporting Evidence: GO_REF:0000108 file:human/CLN5/CLN5-source-evidence.json |
| GO:0007040 lysosome organization | IBA GO_REF:0000033 | ACCEPT | Summary: Retain the curated lysosome-organization role. Reason: Mouse Cln5 knockout has experimentally documented lysosomal storage abnormalities, and the curated node retains that organizational role. Direct CLN5 lipid-enzyme capacity provides a coherent contribution to lysosomal membrane composition; the phenotype alone is not used to invent a new process. The original mouse identity and node are preserved. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001809699 SUPPORTS TRANSFER The actual mouse experimental premise and independently established target lysosomal biochemistry support the curated role; historical node placement remains uninspected. Supporting Evidence: GO_REF:0000033 file:human/CLN5/CLN5-source-evidence.json |
| GO:0007042 lysosomal lumen acidification | IMP PMID:11722572 Elevated lysosomal pH in neuronal ceroid lipofuscinoses (NCL... | UNDECIDED | Summary: The patient-cell pH effect is established, but CLN5 acidification participation remains unresolved. Reason: The recovered original Methods, Table 1 and Results measure lysosomal pH in one CLN5 patient fibroblast line carrying the homozygous 2467(AT) deletion: 4.64 ± 0.18 versus 4.02 ± 0.06 in the control, with normal cytoplasmic pH. This is positive evidence for a genotype-associated lysosomal pH defect. However, the Discussion explicitly leaves direct and indirect mechanisms open; it does not establish that CLN5 itself performs a lysosomal pH-lowering step. Keep the source-specific participation assertion unresolved rather than assuming either direct involvement or a demonstrated downstream consequence. Unlike the maturation experiments, this assay does not resolve which entity performs the relevant step. Supporting Evidence: |
| GO:0007420 brain development | IEP PMID:10992246 CLN-1 and CLN-5, genes for infantile and variant late infant... | UNDECIDED | Summary: The source-specific brain development assignment needs fuller resolution. Reason: The authentic original abstract positively reports CLN5 expression in developing human brain and postmitotic migrating neuroblasts. Its unavailable full text prevents assessment of any additional evidence for a CLN5-performed developmental step. Preserve the original IEP assertion as unresolved rather than converting expression or later neurodegeneration into a specific developmental mechanism. Supporting Evidence: |
| GO:0008474 palmitoyl-(protein) hydrolase activity | EXP PMID:35427157 Cln5 represents a new type of cysteine-based S-depalmitoylas... | KEEP AS NON CORE | Summary: Purified-enzyme and deficient-cell lysate assays support non-core thioesterase capacity. Reason: Purified human CLN5 cleaves palmitoyl-thioester probes with mutant and inhibitor controls. Figure 5 adds cellular evidence: CLN5-deficient neural progenitor cell lysates show less DPP-5 conversion, which the authors interpret as a substantial neuronal thioesterase contribution. The Results describe mouse cells whereas the legend says human; that inconsistency remains unresolved. These positive observations support retention, while the synthetic readout does not identify an endogenous protein substrate. The Discussion itself acknowledges this physiological-substrate limitation. The coupled MU assay includes added beta-glucosidase and does not demonstrate CLN5 glycoside hydrolysis. Supporting Evidence: PMID:35427157 showed greatly diminished thioesterase activity when compared to wild-type cells |
| GO:0008474 palmitoyl-(protein) hydrolase activity | IEA GO_REF:0000003 | KEEP AS NON CORE | Summary: Retain the EC-mapped thioesterase capacity with its cellular and substrate limits. Reason: The EC mapping is grounded in the measured palmitoyl-thioesterase activity: purified CLN5 has mutant-sensitive probe turnover, and CLN5-deficient NPC lysates show reduced DPP-5 activity in Figure 5. The authors infer a neuronal physiological contribution, but the assay remains a synthetic-probe readout and no endogenous protein substrate is identified. Results label the NPCs mouse and the legend labels them human. Retain the activity as non-core with those limits; neither the cellular result nor the Discussion caveat should be omitted. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: EC:3.1.2.22 SUPPORTS TRANSFER The EC mapping retains the measured probe activity, without claiming a demonstrated endogenous protein substrate. |
| GO:0016020 membrane | EXP PMID:24038957 Topology and membrane anchoring of the lysosomal storage dis... | MODIFY | Summary: Specify the lysosomal membrane association of mature CLN5. Reason: The original abstract describes precursor topology and cleavage, followed by mature CLN5 association with lysosomal membranes through an amphipathic region. This supports a more informative compartment than membrane, without asserting that the mature protein remains transmembrane. Proposed replacements: lysosomal membrane Supporting Evidence: |
| GO:0016020 membrane | IDA PMID:12134079 Neuronal ceroid lipofuscinoses are connected at molecular le... | KEEP AS NON CORE | Summary: Retain the membrane-associated precursor observation. Reason: The original fractionation experiments detect the longest CLN5 translation product with membranes, while shorter forms behave differently. Preserve this positive construct-specific observation as non-core; it is not a claim that every mature or processed form is integral to a membrane. Supporting Evidence: |
| GO:0016020 membrane | IDA PMID:28442266 CLN5 is cleaved by members of the SPP/SPPL family to produce... | KEEP AS NON CORE | Summary: Retain membrane association at the precursor stage. Reason: The original abstract identifies a membrane-associated precursor cleaved by SPPL3 and a released soluble lysosomal fragment. The broad membrane term is valid for that precursor stage but is not the defining location of all processed CLN5 molecules. Supporting Evidence: |
| GO:0016020 membrane | IEA GO_REF:0000044 | MODIFY | Summary: Specify the supported lysosomal membrane compartment. Reason: The subcellular-vocabulary membrane mapping is biologically compatible with CLN5, but direct localization and luminal membrane-association evidence resolve the lysosomal compartment. Precursor and soluble forms remain distinct; the refinement does not impose integral-membrane topology. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: UniProtKB-SubCell:SL-0162 SUPPORTS TRANSFER The broad location is supported; target experiments provide the lysosomal membrane context. Proposed replacements: lysosomal membrane Supporting Evidence: GO_REF:0000044 file:human/CLN5/CLN5-source-evidence.json |
| GO:0016020 membrane | NAS PMID:9662406 CLN5, a novel gene encoding a putative transmembrane protein... | KEEP AS NON CORE | Summary: Retain the broad membrane context with later processing qualifications. Reason: The original cloning report proposed membrane association from sequence, and later experiments substantiate membrane-associated precursor and luminally attached forms. The historical prediction is retained as non-core without promoting it to a permanent transmembrane topology for mature CLN5. |
| GO:0016798 hydrolase activity, acting on glycosyl bonds | IBA GO_REF:0000033 | UNDECIDED | Summary: The glycosyl-hydrolase assay and inherited scope remain unresolved. Reason: The exact Dictyostelium donor has an IDA annotation from PMID:29128403, whose authentic abstract explicitly reports activity for both Dictyostelium and human CLN5. The full substrate, purification and control assays were not recovered, and historical PAINT placement was not reconstructed. This is positive evidence with unresolved mechanistic scope, not a wrong-organism or donor-count objection; the later coupled thioesterase assay does not refute this separate report. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN001809699 UNRESOLVED The experimental donor premise is authenticated, but exact glycosyl-bond assay specificity and ancestral placement remain unverified. Supporting Evidence: GO_REF:0000033 file:human/CLN5/CLN5-source-evidence.json |
| GO:0022008 neurogenesis | IEP PMID:10992246 CLN-1 and CLN-5, genes for infantile and variant late infant... | UNDECIDED | Summary: The source-specific neurogenesis assignment needs fuller resolution. Reason: The authentic original abstract positively reports CLN5 expression in developing human brain and postmitotic migrating neuroblasts. Its unavailable full text prevents assessment of any additional evidence for a CLN5-performed developmental step. Preserve the original IEP assertion as unresolved rather than converting expression or later neurodegeneration into a specific developmental mechanism. Supporting Evidence: |
| GO:0030163 protein catabolic process | NAS PMID:10740217 Batten's disease: clues to neuronal protein catabolism in ly... | MARK AS OVER ANNOTATED | Summary: Broad NCL catabolism speculation does not establish a CLN5 protein-breakdown step. Reason: The original review presents the functions of CLN3 and CLN5 as unknown and proposes that NCL proteins may facilitate modified-protein catabolism. Later direct CLN5 assays establish lipid/thioester chemistry, while the tested protein-proteolysis assays were inconclusive. The source-specific protein-catabolic assertion exceeds the demonstrated role; this does not deny indirect effects on lysosomal proteostasis. |
| GO:0042147 retrograde transport, endosome to Golgi | IMP PMID:22431521 The role of ceroid lipofuscinosis neuronal protein 5 (CLN5) ... | KEEP AS NON CORE | Summary: Retain the experimentally supported retromer-dependent trafficking context. Reason: CLN5 depletion decreases retromer membrane recruitment and diverts sortilin and CI-MPR toward degradation; a silencing-resistant CLN5 construct rescues the recruitment phenotype. This supports the original transport involvement as non-core context. It does not establish CLN5 as the vesicle coat, a cytosolic scaffold or a direct Rab7 exchange factor. Supporting Evidence: |
| GO:0042551 neuron maturation | NAS PMID:10992246 CLN-1 and CLN-5, genes for infantile and variant late infant... | UNDECIDED | Summary: The source-specific neuron maturation assignment needs fuller resolution. Reason: The authentic original abstract positively reports CLN5 expression in developing human brain and postmitotic migrating neuroblasts. Its unavailable full text prevents assessment of any additional evidence for a CLN5-performed developmental step. Preserve the original NAS assertion as unresolved rather than converting expression or later neurodegeneration into a specific developmental mechanism. Supporting Evidence: |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:10992246 CLN-1 and CLN-5, genes for infantile and variant late infant... | UNDECIDED | Summary: The exact perinuclear localization evidence remains inaccessible. Reason: The original abstract confirms expression in developing human neurons but does not expose the subcellular imaging underlying this IDA assertion. The unavailable original figures and Methods prevent a source-specific adjudication. Preserve the positive curated assertion as unresolved, without inferring that a perinuclear pool is absent. Supporting Evidence: |
| GO:0051604 protein maturation | IDA PMID:20052765 The neuronal ceroid lipofuscinosis protein CLN5: new insight... | MARK AS OVER ANNOTATED | Summary: CLN5 maturation is demonstrated, but its own processing activity is not. Reason: The authentic original report describes proteolytic processing of CLN5 into a mature lysosomal protein. The author thesis and later directly read pulse-chase and protease-inhibitor experiments corroborate CLN5 as the processed substrate. They do not establish that CLN5 catalyzes, scaffolds or otherwise performs maturation of itself or another protein; the original source is retained while the participant assignment is considered over-annotated. |
| GO:0052816 long-chain fatty acyl-CoA hydrolase activity | IDA PMID:35427157 Cln5 represents a new type of cysteine-based S-depalmitoylas... | UNDECIDED | Summary: The acyl-CoA-specific substrate assignment remains unresolved. Reason: The accessible primary body reports screening acyl esters, acyl acid amides and acyl thioesters, followed by detailed palmitoyl-thioester probe assays. That screen is a relevant place to investigate the original acyl-CoA annotation, but the named probes are not acyl-CoA substrates. No long-chain acyl-CoA experiment was verified in the read body or Methods, and the supplementary substrate details remain inaccessible. Keep the original IDA unresolved; chemical membership in the thioester class does not establish that palmitoyl-CoA was tested. |
| GO:0052816 long-chain fatty acyl-CoA hydrolase activity | IEA GO_REF:0000107 | UNDECIDED | Summary: The orthology transfer inherits the unresolved acyl-CoA substrate scope. Reason: The authenticated mouse donor has direct and propagated annotations for this activity, including PMID:35427157; the transfer is not source-free or circular. The original body names an acyl-thioester screen, but the accessible detailed assays use synthetic probes without CoA. Because the supplementary substrate details were not recovered, the acyl-CoA-specific scope remains unresolved rather than being inferred from the broad substrate class. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q3UMW8 UNRESOLVED Positive direct donor curation exists, but the CoA-specific experiment remains unverified because the relevant supplement was inaccessible. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | UNDECIDED | Summary: The original exosome target-table entry remains unverified. Reason: The source describes proteomics of extracellular vesicles isolated from expressed prostatic secretions in urine. Its authentic main Methods and Results are accessible, but the original supplementary target table could not be recovered to verify the CLN5 detection. Retain the curated HDA assertion as unresolved without a contamination or misattribution claim. Independently, PMID:11971870 reports expressed CLN5 in the culture medium of transfected BHK-21 cells. That supports secretion as a plausible context but does not identify CLN5 in the original exosome table or distinguish soluble secretion from vesicular packaging. |
| GO:0098734 obsolete macromolecule depalmitoylation | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | Summary: The cellular probe result supports physiological relevance without identifying a macromolecular substrate. Reason: Figure 5 shows reduced DPP-5 turnover in CLN5-deficient NPC lysates, and the authors interpret this as a neuronal thioesterase contribution. This is positive cellular evidence, not an absent physiology experiment. However, the readout still uses a synthetic probe, no endogenous depalmitoylated macromolecule is identified, and the Discussion explicitly limits physiological interpretation of the artificial-substrate assays. The Results/legend mouse-versus-human discrepancy also remains unresolved. Extending this evidence to the asserted macromolecule-depalmitoylation process exceeds the demonstrated substrate scope. The original obsolete identifier is preserved; obsolescence is not the reason for this decision. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: GO:0008474 SUPPORTS SOURCE BUT NOT TARGET Purified-enzyme and deficient-cell synthetic-probe results support the source activity, but do not identify a depalmitoylated macromolecule for the target process. Supporting Evidence: GO_REF:0000108 PMID:35427157 we cannot assess the physiological importance of their activities file:human/CLN5/CLN5-source-evidence.json |
| GO:0160121 bis(monoacylglycero)phosphate synthase activity | IDA PMID:37708259 The Batten disease gene product CLN5 is the lysosomal bis(mo... | ACCEPT | Summary: Retain directly demonstrated BMP-forming transacylase capacity. Reason: The original abstract reports CLN5-mediated BMP synthesis, and an independent later purified-enzyme study directly reproduces formation of R,racemic BMP while finding no S,S-BMP production. Retain the molecular capacity without assigning the PLD3/4 stereoinversion reaction or universal control of cellular BMP pools to CLN5. Current GO and RHEA reaction text differ in glycerol numbering; the original GO identifier is preserved and that discrepancy is documented explicitly. Supporting Evidence: PMID:39423811 it can use R,racemic-lyso-PG to synthesize R,racemic-BMP file:human/CLN5/CLN5-source-evidence.json |
| GO:1904426 positive regulation of GTP binding | IMP PMID:22431521 The role of ceroid lipofuscinosis neuronal protein 5 (CLN5) ... | KEEP AS NON CORE | Summary: Retain the source-specific increase in Rab7 GTP loading. Reason: CLN5 depletion reduces Rab7 GTP-photoprobe labeling and RILP capture, while Rab5 loading is unchanged. These cellular results support positive regulation of GTP binding as non-core trafficking context. They do not identify a purified nucleotide-exchange reaction or distinguish direct CLN5 action from intermediary membrane proteins. Supporting Evidence: |
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Download this section (compressed HTML)Q: Which BMP stereoisomers does endogenous human CLN5 produce, and how should the inconsistent GO:0160121 and RHEA:77619 glycerol numbering be reconciled?
Q: What natural protein or lipid substrates account for the measured synthetic-probe thioesterase activity, and which original experiment supports the acyl-CoA-specific annotations?
Q: Which glycosyl-bond substrate and purification controls underlie the reported human and Dictyostelium CLN5 glycosidase activity?
Q: How does luminal CLN5 affect cytosolic Rab7 activation and retromer recruitment, and is the connection mediated by another membrane protein?
Q: Which assays in the original maturation study distinguish CLN5 being processed from CLN5 performing a maturation step on another protein?
Q: Does the original CLN5 mannose-6-phosphate affinity study contain any direct CLN5 sugar-recognition experiment beyond capture of its covalent glycans by the receptor?
Experiment: Compare sequence-defined purified human CLN5 with PLD3 and PLD4 using stereochemically resolved LPG and BMP standards, alongside inactive mutants and matched enzyme-free controls.
Experiment: Test candidate natural palmitoylated substrates and acyl-CoA species directly with purified CLN5, separating thioester cleavage from any auxiliary glucosidase reaction.
Experiment: Measure Rab7 loading and receptor recycling after endogenous CLN5 rescue with catalytically inactive but normally localized variants, while testing candidate transmembrane intermediates.
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