ACTR10 (ARP11, also called ACTR11/ARP10/hARP11) is the pointed-end subunit of dynactin, the ~1.2 MDa multiprotein activator of cytoplasmic dynein-1. It is a highly divergent member of the actin family: it retains the actin fold, and its nucleotide- and metal-binding site is occupied by ATP or ADP with Mg2+ in cryo-EM structures of the complex, but it has lost the subdomain-2 surface loop that actin uses at its pointed-end face. As a result ACTR10 cannot polymerise or be polymerised past, and instead caps the pointed end of dynactin's actin-like ACTR1A/beta-actin minifilament, terminating the filament and setting the end of the complex. Docked onto that filament end, ACTR10 is also the platform on which the remaining pointed-end subunits DCTN4/p62, DCTN5/p25 and DCTN6/p27 assemble, and it is required for the structural integrity of dynactin as a whole: cells depleted of ACTR10 lose essentially all assembled dynactin and show the dispersal of endosomes and the spindle defects expected of dynein-dynactin loss. The pointed end formed around ACTR10 is a cargo- and adaptor-facing surface. In vertebrate neurons ACTR10 couples mitochondria to the dynein-dynactin motor and is required for retrograde axonal transport of mitochondria and hence for normal mitochondrial distribution between soma and axon terminals; loss of the protein also produces the general dynein-dynactin phenotypes of disturbed melanosome distribution, photoreceptor degeneration and mislocalised myelin basic protein mRNA in oligodendrocytes. ACTR10 is ubiquitously expressed and acts throughout the cytoplasm, wherever dynactin activates dynein for minus-end-directed transport.
Definition: The binding of a protein to the pointed (minus) end of the actin-related protein 1 (Arp1/ACTR1A) minifilament of the dynactin complex, preventing further addition, exchange or removal of filament subunits and thereby defining the pointed extremity of the complex.
Justification: GO cannot currently express the event ACTR10 performs, and the mismatch is one of scope rather than of missing biology. The nearest existing term, GO:0051694 pointed-end actin filament capping, is defined as "The binding of a protein or protein complex to the pointed (or minus) end of an actin filament, thus preventing the addition, exchange or removal of further actin subunits", and GO's actin filament (GO:0005884) is "A filamentous structure formed of a two-stranded helical polymer of the protein actin and associated proteins". Dynactin's backbone is something else by GO's own definition (GO:0005869): "an actin-like 40 nm filament composed of actin-related protein" - eight Arp1/ACTR1A subunits plus a single beta-actin. The subunits whose addition Arp11 blocks are therefore Arp1, not actin, so GO:0051694 as written describes a different event from the one Arp11 performs. The argument is about grain and context, not about a capacity Arp11 lacks: Eckley and Schroer tested Arp11 against conventional actin and found it could coassemble, and predicted from its conserved barbed-end face that it can interact with filament pointed ends generally (PMID:12857853). What GO is missing is therefore a term for capping the Arp1 minifilament specifically, not a prohibition on relating Arp11 to actin. The only dynactin-specific capping term GO ever had, GO:0005870, cannot express it either: it is a cellular-component term for the CapZ heterodimer at the opposite (barbed) end, so it is about the wrong end of the filament and the wrong aspect regardless of its status. Its status is in fact obsolete - QuickGO returns isObsolete true and renders the label as "obsolete actin capping protein of dynactin complex" with a definition prefixed "OBSOLETE.", and OLS reports term_replaced_by GO:0008290 F-actin capping protein complex, which is again barbed-end CapZ and again a cellular component. The event is well enough characterised to warrant a term: cryo-EM shows a single Arp11 subunit capping both protofilaments, blocking subunit addition on one because its subdomain-2 loop is too short and sterically on the other, and Arp11 is the only subunit that directly caps that end. Two placements are offered rather than one, because the choice is an editorial call about GO:0051693's intended scope. If GO:0051693 actin filament capping is meant to cover filaments built from any actin-family protein - which its current wording, "an actin filament ... further actin subunits", does not say - the new term is its child, as proposed here, and it would also serve the yeast ortholog Arp10 and the fungal Arp11 proteins and give the two ends of dynactin's filament parallel representation. If GO:0051693 is to stay strictly F-actin, the new term belongs instead under GO:0065003 protein-containing complex assembly, since terminating the Arp1 filament is a step in building dynactin. Either way the alternative - widening GO:0051693 and GO:0051694 in place - would also resolve it.
Parent term: actin filament capping
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | REMOVE | Summary: Every WITH/FROM source on this row is a nuclear actin-related protein from a different subfamily, not an ACTR10/ARP11 ortholog: budding yeast ARP9 (Q05123) and Candida ARP9 (Q5A9X7), which are subunits of the SWI/SNF and RSC chromatin-remodelling complexes; mouse ACTL7A (Q9QY84), a testis actin-like protein; and an unreviewed Trypanosoma brucei entry named only "Actin-like protein, putative". All four carry their own experimental nucleus annotations, so the source annotations are correct and it is the transfer that fails. The mechanism is visible in the WITH/FROM field itself: dynactin membership and mitochondrial transport were propagated from ARP11-specific nodes (PTN000232945, PTN000232947), whereas nucleus came from PTN008986520, a deeper node in PTHR11937 that groups ARP11 with the nuclear ARPs. ACTR10 is a subunit of a cytoplasmic 1.2 MDa complex with a single UniProt location, "Cytoplasm, cytoskeleton", and an independent check in Human Protein Atlas immunofluorescence puts 3/4 human nuclear ARPs but 0/3 human dynactin ARPs in a nuclear compartment. Reason: Paralog transfer across a subfamily boundary within the actin family, carrying the strong is_active_in qualifier. There is no evidence of any kind that human ACTR10 acts in the nucleus, and dynactin has no nuclear form. The sources are sound for themselves, so this is a propagation failure rather than a weak source. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG COMPARTMENT OR COMPLEX MISMATCH Sources checked: CGD:CAL0000196900 · Candida albicans ARP9 (Q5A9X7, unreviewed/TrEMBL) SUPPORTS SOURCE BUT NOT TARGET Candida ARP9, a nuclear chromatin-remodelling actin-related protein. QuickGO reports IDA for nucleus on this entry, so the source annotation is experimental; the entry is unreviewed, so its protein name is not itself evidence. MGI:MGI:1343051 · mouse Actl7a (Q9QY84, Swiss-Prot) SUPPORTS SOURCE BUT NOT TARGET Actin-like protein 7A, a testis-restricted actin-like protein with its own IDA/EXP nucleus annotations and an IDA for male germ cell nucleus. A distinct subfamily from ARP11 with no dynactin role. PANTHER:PTN008986520 · PANTHER internal tree node NOT RELEVANT Not a protein but the ancestral node PAINT annotated. Notably a different and deeper node than the ARP11-specific nodes used for the dynactin-complex and mitochondrial-transport rows, which is where the over-propagation enters. SGD:S000004636 · S. cerevisiae ARP9 (Q05123, Swiss-Prot) SUPPORTS SOURCE BUT NOT TARGET Arp9p is a subunit of the SWI/SNF (GO:0016514, IDA) and RSC (GO:0016586, IDA) chromatin-remodelling complexes, with nucleus IDA. A bona fide nuclear ARP and a paralog, not the ARP11 ortholog - the S. cerevisiae ARP11 ortholog is ARP10/Q04549, which is used on the GO:0005200 row of this same gene. UniProtKB:Q57ZL0 · Trypanosoma brucei "Actin-like protein, putative" (unreviewed/TrEMBL) SOURCE WEAK OR INFERRED Unreviewed entry with no gene symbol and an automatic by-similarity name; QuickGO does report IDA for nucleus, so the annotation is experimental even though the protein is otherwise uncharacterised and not assignable to an ARP subfamily. Supporting Evidence: file:human/ACTR10/ACTR10-bioinformatics/RESULTS.md - protein sources: 4; with own experimental evidence for this term: 4; with a reviewed (Swiss-Prot) record: 2 file:human/ACTR10/ACTR10-bioinformatics/RESULTS.md Q05123 (Swiss-Prot) Saccharomyces cerevisiae (strain ATCC 204508 / S288c) ARP9 :: Actin-like protein ARP9 file:human/ACTR10/ACTR10-bioinformatics/RESULTS.md - dynactin clade: 0/3 genes with a nuclear compartment in their HPA location list (ACTR10:non-nuclear, ACTR1A:non-nuclear, ACTR1B:non-nuclear) PMID:16291862 consistent with the general pattern of paired Arps engaged in related functions (Arp2/Arp3 and Arp7/Arp9) PMID:42439233 In the nucleus, multiple Arps, actin, and actin-like proteins are incorporated into large ATP-dependent chromatin-remodelling and histone-modifying complexes PMID:42439233 many of which exhibit tissue-specific expression, particularly in the testis, and are associated with spermiogenesis and male fertility file:human/ACTR10/ACTR10-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton |
| GO:0005869 dynactin complex | IBA GO_REF:0000033 | ACCEPT | Summary: Correct and central. All three protein sources on this row are genuine ACTR10 orthologs - mouse Actr10 (Q9QZB7, which carries its own IDA for this term), pig ACTR10 (I3LHK5, the accession behind the pig dynactin cryo-EM series) and C. elegans arp-11 (Q9GYR2, unreviewed but with its own IDA) - and the node used (PTN000232945) is ARP11-specific. Human evidence is now stronger than the annotation records: human dynactin was purified from human cell culture and solved by cryo-EM in 2025, with human ACTR10 (Q9NZ32) modelled as chain J of PDB 9B7J and 9B85, and AP-MS from HEK293T recovering all 11 dynactin subunits. UniProt lists ACTR10 among the four pointed-end subunits and ComplexPortal records it in CPX-26352. Reason: Core. Ortholog-based propagation from sources that carry their own experimental complex-membership annotations, and now independently demonstrable in the human protein by cryo-EM of human dynactin. The one thing worth changing is the evidence code, not the term: an IDA from PMID:40186871 is available and would bring human ACTR10 into line with mouse Actr10, which already has the IDA. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:1891654 · mouse Actr10 (Q9QZB7, Swiss-Prot; cross-reference also maps to 2 TrEMBL entries) SUPPORTS TRANSFER True ortholog with its own IDA for dynactin complex from PMID:10525537. The MGI cross-reference is ambiguous, resolving to three accessions (Q9QZB7 plus TrEMBL A0A1Y7VL71 and A0A1Y7VM21); only the Swiss-Prot entry carries annotations. PANTHER:PTN000232945 · PANTHER internal tree node NOT RELEVANT Tree node rather than a protein. Worth recording that this ARP11-specific node, and not the deeper node used for the nucleus row, is the correct level for ARP11 propagation. UniProtKB:I3LHK5 · pig ACTR10 / Arp10 (Swiss-Prot) SUPPORTS TRANSFER True ortholog and the subject of the pig dynactin cryo-EM series (chain J in 22 PDB entries). It is also the ECO:0000250 source for UniProt's human FUNCTION and SUBUNIT lines. WB:WBGene00016793 · C. elegans arp-11 (Q9GYR2, unreviewed/TrEMBL) SUPPORTS TRANSFER True ortholog with its own IDA for this term. No reviewed UniProt entry exists and the accession is not indexed under xref:wormbase-*, so it was resolved by identifier search; an unreviewed entry is weaker support and its name is an automatic label, but the curated annotation on it is real. Supporting Evidence: file:human/ACTR10/ACTR10-uniprot.txt subunits: ACTR10, DCNT4, DCTN5 and DCTN6. PMID:40186871 By exploiting Dre1 as an affinity reagent, we purified dynactin from human cell culture and solved the first cryo-EM structure of human dynactin. PMID:40186871 all 11 subunits of the host dynactin complex PMID:10525537 The p62 and p27 subunits are associated with two previously undetected dynactin subunits, p25 and a novel actin-related protein, Arp11, in dynactin file:human/ACTR10/ACTR10-bioinformatics/RESULTS.md - protein sources: 3; with own experimental evidence for this term: 3; with a reviewed (Swiss-Prot) record: 2 |
| GO:0005200 structural constituent of cytoskeleton | IBA GO_REF:0000033 | ACCEPT | Summary: This is the fold-propagation row and it needed testing in both directions. The source set is mixed: seven of the ten protein sources are polymerising actins or Arp2/3 subunits (mouse and rat ACTG1, yeast ACT1, two Dictyostelium actins, human ACTR2 and ACTR3), but three are dynactin-relevant - yeast ARP1/centractin (P38696), which builds the dynactin filament, and crucially yeast ARP10 (Q04549), the true S. cerevisiae ARP11 ortholog. All ten carry their own experimental evidence for the term and all ten are Swiss-Prot. The term itself is well scoped for ACTR10 by GO's own classification, since GO:0005869 dynactin complex is a descendant of GO:0015629 actin cytoskeleton; and it is substantively true, because ACTR10 caps and terminates dynactin's actin-like minifilament and is required for the complex to stay assembled at all. What does NOT transfer from the conventional-actin sources is polymerisation. ACTR10 lacks the subdomain-2 loop (20/20 of actin residues 38-57 align to a gap), it binds Arp1 by coprecipitation, and in cells it is found exclusively in dynactin with no free pool. The boundary needs stating carefully rather than overstated: Arp11 was tested against conventional actin and could coassemble with it in vitro, and an Arp2/3-like nucleation role was raised by those authors as a hypothesis - but it was never demonstrated, and they argue Arp1 needs no nucleator, having a critical concentration below 1 nM and assembling without a lag. So no actin-polymerisation or actin-nucleation term is warranted here because none has been shown, not because the capacity is excluded; GOA correspondingly has none. Reason: Core, and correctly scoped. ACTR10's own contribution to dynactin's structural integrity is exactly what this MF expresses, and the enables qualifier follows the established practice for "structural constituent of" terms (as for ribosomal proteins) rather than requiring contributes_to. The term is coarse and a specific pointed-end-capping term would be more informative, but no such term exists in GO. Note that the term proposed in proposed_new_terms is a biological process (its parents GO:0051693 and GO:0065003 are both BP), so even once it exists it could not replace this molecular-function row: it would be an additional annotation in a different aspect, which is why no proposed_replacement_terms is given here. Propagation Review Root cause: NO FAILURE CORE Sources checked: SGD:S000002513 · S. cerevisiae ARP10 (Q04549, Swiss-Prot) SUPPORTS TRANSFER The true budding-yeast ARP11 ortholog and the pointed-end-associated component of yeast dynactin. Its presence makes this an ortholog-supported transfer, not purely a fold-level guess. QuickGO reports IPI for this term on the entry. SGD:S000001171 · S. cerevisiae ARP1 / centractin (P38696, Swiss-Prot) SUPPORTS TRANSFER The actin-related protein that polymerises to form the dynactin minifilament ACTR10 caps; IDA for this term. Directly relevant rather than a generic actin. MGI:MGI:87906 · mouse Actg1 (P63260, Swiss-Prot; cross-reference maps to 5 accessions) SUPPORTS SOURCE BUT NOT TARGET Conventional cytoplasmic actin with IDA. Its "structural constituent" activity is filament formation, which ACTR10 cannot perform, so this source supports the parent term but not the polymerising sense of it. Ambiguous cross-reference: 5 hits, of which only P63260 is reviewed and annotated. RGD:1304556 · rat Actg1 (P63259, Swiss-Prot; cross-reference maps to 2 accessions) SUPPORTS SOURCE BUT NOT TARGET Conventional actin with IDA; same caveat as mouse Actg1. SGD:S000001855 · S. cerevisiae ACT1 (P60010, Swiss-Prot) SUPPORTS SOURCE BUT NOT TARGET Conventional actin with IDA; polymerising sense does not transfer. UniProtKB:P60709 · human ACTB (Swiss-Prot) SUPPORTS SOURCE BUT NOT TARGET Conventional actin with EXP/IDA/IMP. Also the reference sequence used in this review's alignment to locate the actin nucleotide site. UniProtKB:P61158 · human ACTR3 / Arp3 (Swiss-Prot) SUPPORTS SOURCE BUT NOT TARGET Arp2/3-complex subunit with IDA. A different actin-related subfamily whose structural role is filament nucleation. UniProtKB:P61160 · human ACTR2 / Arp2 (Swiss-Prot) SUPPORTS SOURCE BUT NOT TARGET Arp2/3-complex subunit with IDA; same caveat as ACTR3. dictyBase:DDB_G0269234 · Dictyostelium major actin (P07830, Swiss-Prot) SUPPORTS SOURCE BUT NOT TARGET Conventional actin with IDA. dictyBase:DDB_G0289811 · Dictyostelium Actin-10 (Q54GX7, Swiss-Prot) SUPPORTS SOURCE BUT NOT TARGET Conventional actin with IDA. PANTHER:PTN000940351 · PANTHER internal tree node NOT RELEVANT Tree node rather than a protein. Supporting Evidence: PMID:22918948 Arp11 and p62 were found to be essential for preservation of dynactin structure, whereas p150Glued, p27, and p25 were not. PMID:25814576 Only Arp11 directly caps the pointed end PMID:10525537 The predicted structure of Arp11 suggests it will not form filaments by itself and will only interact with filaments of Arp1, or conventional actin, at their pointed ends. PMID:12857853 Like Arp1, cytosolic Arp11 is found only in dynactin, suggesting that Arp11 and free cytosolic actin do not interact significantly. PMID:12857853 We tested the ability of Arp11 to interact with conventional actin and found it could coassemble. PMID:12857853 Arp1 has a vanishingly low critical concentration for polymerization (<1 nM) and assembles without a lag phase, suggesting nucleation is not required PMID:16291862 Using both genetic and biochemical approaches, we demonstrate that Arp10p is the functional yeast homologue of Arp11, suggesting the possible existence of a pointed-end complex in yeast. PMID:16291862 Conversely, Arp10p stabilizes the dynactin complex by association with the Arp1p filament pointed end. file:human/ACTR10/ACTR10-bioinformatics/RESULTS.md Q04549 (Swiss-Prot) Saccharomyces cerevisiae (strain ATCC 204508 / S288c) ARP10 :: Actin-like protein ARP10 file:human/ACTR10/ACTR10-bioinformatics/RESULTS.md In the alignment above, 20/20 of actin positions 38-57 align to a gap in human ACTR10. |
| GO:0098958 retrograde axonal transport of mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Propagated from a single but excellent source: zebrafish actr10 (Q7ZVU0), the true ortholog, whose annotation rests on a forward-genetic loss-of-function allele with an IMP. In actr10 mutants mitochondria, and specifically not the other cargoes assayed, accumulate at microtubule plus ends because they fail to attach to the dynein-dynactin complex; an Actr10 construct lacking the dynactin-binding domain still binds mitochondria, indicating ACTR10 is the coupling element rather than merely a structural subunit in this process. Follow-up work shows the homeostatic consequence, with mitochondria depleted from the soma and accumulated in axon terminals. Two caveats worth carrying forward: the zebrafish cross-reference is ambiguous, resolving to two unreviewed accessions of which only Q7ZVU0 is annotated; and a second actr10 allele shows the generic dynein-dynactin phenotypes (photoreceptor loss, aberrant melanosome distribution, mislocalised mbp mRNA), so ACTR10 is not a mitochondria-only subunit. Reason: Sound ortholog-based propagation from a real loss-of-function experiment, and the best-characterised in-vivo role of the protein. It is retained as core because the zebrafish work identifies ACTR10 as the specific subunit mediating the mitochondria-dynactin link, not merely as a passenger in general dynactin function; the broader dynein-dynactin transport role is captured in core_functions. Propagation Review Root cause: NO FAILURE CORE Sources checked: ZFIN:ZDB-GENE-040426-768 · zebrafish actr10 (Q7ZVU0, unreviewed/TrEMBL; cross-reference maps to 2 accessions) SUPPORTS TRANSFER True ortholog carrying its own IMP for this term, from the actr10nl15 loss-of-function allele. The UniProt entry is unreviewed, so its protein name carries no weight, but the curated IMP does. The second hit (A0A8N7UZZ7) carries no annotations. PANTHER:PTN000232947 · PANTHER internal tree node NOT RELEVANT ARP11-specific tree node rather than a protein. Supporting Evidence: PMID:28414272 Analysis of cargo localization and movement in the actr10 mutant revealed clustering of mitochondria, but not other cargos analyzed, at microtubule plus ends due to failed retrograde mitochondrial movement. PMID:28414272 Furthermore, we demonstrated that abnormal mitochondrial movement in actr10 mutants is due to failed attachment of mitochondria to the dynein-dynactin complex in the absence of Actr10. PMID:28414272 Importantly, Actr10 engineered to lack the dynactin binding domain maintains mitochondrial interaction, hinting at a specific role for Actr10 in mediating dynactin-mitochondria interaction. PMID:33376159 In contrast, inhibition of retrograde mitochondrial movement in the actr10nl15 mutant line leads to a significant reduction of mitochondrial load in the soma and an accumulation of this organelle in axon terminals file:human/ACTR10/ACTR10-bioinformatics/RESULTS.md - protein sources: 1; with own experimental evidence for this term: 1; with a reviewed (Swiss-Prot) record: 0 file:human/ACTR10/ACTR10-deep-research-affinage.md Actr10 (Arp11 subunit of dynactin) is required for dynactin-mitochondria interaction and mitochondrial retrograde transport in axons. |
| GO:0005856 cytoskeleton | IEA GO_REF:0000044 | MODIFY | Summary: Mapped from the UniProt subcellular-location keyword SL-0090, which in turn renders the line "Cytoplasm, cytoskeleton" - itself an ECO:0000250 by-similarity statement from pig I3LHK5. The location is not wrong, but GO:0005856 is a strict ancestor of GO:0005869 dynactin complex (confirmed from the QuickGO ancestor list for GO:0005869, which contains GO:0005856, GO:0015629 actin cytoskeleton and GO:0015630 microtubule cytoskeleton), and ACTR10 already carries the dynactin-complex term. The coarse parent therefore adds nothing. Reason: Redundant coarse ancestor of an annotation the gene already has. The informative statement is complex membership, which belongs in GO:0005869; keeping both makes the location look independently supported when it is the same fact stated less precisely. To be explicit about what the replacement means downstream: the gene already carries GO:0005869 as part_of by IBA, and the UniProt SubCell pipeline behind GO_REF:0000044 cannot emit a complex term from the keyword SL-0090, so this is in practice a drop-the-redundant-ancestor recommendation - the replacement collapses into the existing part_of row rather than creating a second, located_in one. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB-SubCell:SL-0090 · UniProt subcellular location keyword "Cytoskeleton" SUPPORTS TRANSFER The keyword mapping is applied correctly; the issue is only that the resulting term is a strict ancestor of the dynactin-complex annotation the gene already carries. The underlying UniProt location line is itself by-similarity from pig ACTR10. Proposed replacements: dynactin complex Supporting Evidence: file:human/ACTR10/ACTR10-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton |
| GO:0007010 cytoskeleton organization | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: An automatic inter-ontology inference whose sole input is this gene's own GO:0005200 IBA row. It is defensible in the weak sense that ACTR10 is required for assembly of dynactin, which GO classifies under both the actin and microtubule cytoskeleton, but ACTR10 does not organise or remodel the cytoskeleton in any direct sense: it caps one end of a nine-subunit minifilament inside a motor-adaptor complex. Reason: True but uninformative, and carries no evidence independent of the GO:0005200 row it is derived from. Retained because it is not incorrect, but it should not be read as ACTR10 having a cytoskeletal-remodelling role. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: GO:0005200 · structural constituent of cytoskeleton (this gene's own IBA row) CIRCULAR OR REDUNDANT The inference's only input is another propagated annotation on the same gene, so the row adds no independent support. Supporting Evidence: PMID:22918948 Arp11 and p62 were found to be essential for preservation of dynactin structure, whereas p150Glued, p27, and p25 were not. |
| GO:1904115 axon cytoplasm | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Inferred automatically from this gene's GO:0098958 row, which is itself an IBA from zebrafish. The location is biologically sound - dynactin drives retrograde transport along axons and the zebrafish work images Actr10-dependent mitochondrial movement in axons - but the row is an inference over an inference and there is no human axonal localisation data for ACTR10. Reason: Correct but neither independent nor general: it is a cell-type-restricted location derived logically from a propagated BP annotation. Keep, since dynactin genuinely operates in axonal cytoplasm, but do not count it as separate evidence. Propagation Review Root cause: EVIDENCE CIRCULAR OR REDUNDANT Failure modes: CIRCULAR PROPAGATION CONTEXT OR TISSUE MISMATCH Sources checked: GO:0098958 · retrograde axonal transport of mitochondrion (this gene's own IBA row) CIRCULAR OR REDUNDANT The inference chains off an IBA rather than any direct observation, so the axonal location inherits all the uncertainty of the zebrafish transfer and adds none of its own support. Supporting Evidence: PMID:33376159 Previous work from our group identified Actr10 as an important link between dynein and mitochondria. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: WITH/FROM resolves to Q9UJ70, human NAGK (N-acetyl-D-glucosamine kinase), from the HI-II-14 yeast two-hybrid interactome. UniProt records the interaction with NbExp=3 from IntAct alone. NAGK has a reported non-catalytic role at the dynein light chain DYNLL1, but there is no independent evidence linking it to dynactin or to the pointed-end complex, and no structural or biochemical follow-up on an ACTR10-NAGK contact exists. Reason: Bare protein binding from a single high-throughput two-hybrid screen with an unreplicated and mechanistically unexplained partner. Nothing informative can be substituted, so the row is flagged rather than replaced. Supporting Evidence: file:human/ACTR10/ACTR10-uniprot.txt Q9NZ32; Q9UJ70: NAGK; NbExp=3 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: WITH/FROM resolves to Q15323, human KRT31 (keratin, type I cuticular Ha1), from the HuRI yeast two-hybrid map. KRT31 is a hair-cuticle keratin whose expression is restricted to the hair shaft, so it shares no cell with cytoplasmic dynactin, and keratins are a well-known sticky partner class in two-hybrid screens. Reason: Bare protein binding from a single two-hybrid screen with a partner that has no plausible shared compartment or expression domain with ACTR10. Not evidence of any ACTR10 function. Supporting Evidence: file:human/ACTR10/ACTR10-uniprot.txt Q9NZ32; Q15323: KRT31; NbExp=3 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: WITH/FROM resolves to Q9UJW0, human DCTN4/p62 - ACTR10's direct neighbour in dynactin's pointed-end complex, and the most informative of the three IPI rows. The contact is independently established beyond the two-hybrid screen: chemical cross-linking of purified dynactin places Arp11 in direct contact with p62 and p25, the two proteins are jointly required for dynactin to remain assembled, and cryo-EM shows the p62 saddle wrapping around Arp11 at the filament end. The functional content of the interaction is that ACTR10 is the structural platform on which the pointed-end module is built, which is what GO:0005200 expresses; bare protein binding does not. Reason: A real, structurally validated intra-complex contact, so the row should be kept but made informative. The replacement is not proposed on the two-hybrid result alone: it rests on the cryo-EM architecture and on the cross-linking and RNAi data showing that the Arp11-p62 pair holds dynactin together. Per project guidance, bare protein binding is replaced with a term that says something about function. Proposed replacements: structural constituent of cytoskeleton Supporting Evidence: file:human/ACTR10/ACTR10-uniprot.txt Q9NZ32; Q9UJW0: DCTN4; NbExp=3 PMID:33734450 The p62 saddle wraps around the Arp11 subunit at the end of dynactin PMID:22918948 These results indicate Arp11 contacts both p62 and p25 directly PMID:22918948 Together these approaches revealed that the pointed-end complex contains two distinct binding activities, comprising the subunit pairs p62/Arp11 and p27/p25. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2213248 | ACCEPT | Summary: Reactome places dynactin, and hence ACTR10, in the cytosol as a participant in transport of antigen-loaded MHC class II molecules to the cell surface. The compartment is correct: ACTR10 has no signal peptide, no transmembrane segment and no lipid anchor, and dynactin is a soluble cytoplasmic complex. This is the first of five rows carrying the same term from five different Reactome reactions. Reason: Correct compartment, and the compartment in which ACTR10 actually functions. Retained as the cytosolic-location annotation for the gene; the more informative location statement remains dynactin-complex membership, and the four further cytosol rows restate this same fact from other Reactome reactions. Supporting Evidence: file:human/ACTR10/ACTR10-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6809003 | ACCEPT | Summary: Duplicate cytosol assignment, here from the reaction in which ERGIC-to-Golgi vesicles bind dynein:dynactin. Correct compartment for a soluble dynactin subunit; the reaction is a genuine dynactin function, but the only GO statement extracted from it is a location the gene already has. Reason: Correct compartment, accepted for consistency with the other cytosol rows; it is the same location restated from a second Reactome reaction rather than independent evidence, and the informative location statement remains dynactin-complex membership. Supporting Evidence: file:human/ACTR10/ACTR10-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6809006 | ACCEPT | Summary: Duplicate cytosol assignment, from the Golgi vesicle-tethering reaction. Correct compartment, no functional content for ACTR10. Reason: Correct compartment, accepted for consistency with the other cytosol rows; it is the same location restated from a third Reactome reaction rather than independent evidence, and the informative location statement remains dynactin-complex membership. Supporting Evidence: file:human/ACTR10/ACTR10-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8849350 | ACCEPT | Summary: Duplicate cytosol assignment, from the reaction in which RAB6:GTP displaces PAFAH1B1/LIS1 from the dynein:dynactin complex. Correct compartment, no functional content for ACTR10 specifically. Reason: Correct compartment, accepted for consistency with the other cytosol rows; it is the same location restated from a fourth Reactome reaction rather than independent evidence, and the informative location statement remains dynactin-complex membership. Supporting Evidence: file:human/ACTR10/ACTR10-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8849353 | ACCEPT | Summary: Duplicate cytosol assignment, from the reaction in which dynein drives COPI-independent Golgi-to-ER retrograde traffic. Notable as the clearest case where Reactome records a real dynactin-dependent process from which only a location term has reached GO for ACTR10. Reason: Correct compartment, accepted for consistency with the other cytosol rows; it is the same location restated from a fifth Reactome reaction rather than independent evidence. Whether pan-dynactin biological processes such as Golgi-to-ER retrograde transport should be propagated to individual structural subunits is a curation-policy question raised in suggested_questions rather than acted on here. Supporting Evidence: file:human/ACTR10/ACTR10-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798751 | REMOVE | Summary: Follows from ACTR10's inclusion in Reactome's azurophil granule lumen protein set, which Reactome's Neutrophil degranulation pathway derives from bulk neutrophil granule proteomics. ACTR10 has no signal peptide and no transmembrane segment - the UniProt feature table contains only a CHAIN, three sequence conflicts and secondary-structure features - and its only recorded location is "Cytoplasm, cytoskeleton". A subunit buried at the pointed end of a 1.2 MDa cytosolic complex has no route into the secretory pathway. The assignment is also not a property of dynactin, and this is now computed rather than asserted. Across the 11 canonical subunits named in UniProt's SUBUNIT line - DCTN1, DCTN2 and DCTN3 in the shoulder, ACTR1A and ACTB in the filament, CAPZA1 and CAPZB at the barbed end, ACTR10, DCTN4, DCTN5 and DCTN6 at the pointed end - exactly one, ACTR10, carries any annotation originating from Reactome's Neutrophil degranulation route, and ACTR10 alone is annotated to azurophil granule lumen. Two near-misses are worth stating because they would otherwise inflate the count: CAPZA1 does carry an extracellular-region TAS, but from R-HSA-879377, an S100B/AGER binding reaction that is not under Neutrophil degranulation at all; and ACTB carries extracellular-region terms only by HDA mass spectrometry, a different artefact class. The one protein that genuinely shares ACTR10's route is ACTR1B, the beta-centractin paralog that substitutes for ACTR1A in a fraction of dynactin and so is a twelfth protein rather than one of the 11 - and, like CAPZA1, one with a large non-dynactin pool. So the pattern is per-protein detection in granule fractions, not secretion of the complex. Reason: Topologically impossible for a cytosolic, membrane-anchorless dynactin subunit, and inconsistent across the complex it belongs to, which marks it as detection of a cytosolic contaminant in a granule fraction rather than genuine secretion. The cost of leaving it is concrete: a 2024 study restated these annotations as ACTR10 biology. Supporting Evidence: file:human/ACTR10/ACTR10-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton PMID:39697424 ACTR10 is predicted to involve in the retrograde axonal transport of mitochondria and is suggested to be present in the cytosol, extracellular region and secretory granules. file:human/ACTR10/ACTR10-bioinformatics/RESULTS.md - canonical subunits whose Reactome TAS comes from the Neutrophil degranulation route: 1/11 (ACTR10) file:human/ACTR10/ACTR10-bioinformatics/RESULTS.md | R-HSA-879377 | The TRTK-12 fragment of F-actin capping protein alpha binds the AGER ligand S100B | **no** | |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6800434 | REMOVE | Summary: Duplicate extracellular-region assignment, here from the ficolin-rich granule exocytosis reaction. The same argument applies: no signal peptide, no transmembrane segment, a single cytoplasmic UniProt location, and none of the other ten canonical dynactin subunits carries an annotation from this Reactome route (CAPZA1's extracellular TAS comes from an unrelated S100B/AGER reaction). Only ACTR1B, the beta-centractin paralog outside the canonical 11, shares it. Reason: Same proteomics-derived artefact as the azurophil-granule route. A dynactin pointed-end subunit is not secreted. Supporting Evidence: file:human/ACTR10/ACTR10-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton |
| GO:0035578 azurophil granule lumen | TAS Reactome:R-HSA-6798751 | REMOVE | Summary: The strongest form of the same error: ACTR10 is placed in the lumen of a secretory granule. Reaching a granule lumen requires translocation into the secretory pathway, for which ACTR10 has neither a signal peptide nor a transmembrane segment; and it would require dissociation from the dynactin complex, which ACTR10 is required to hold together. The annotation traces to bulk granule-fraction proteomics cited by Reactome's Neutrophil degranulation pathway. Reason: A cytosolic actin-fold subunit of dynactin cannot be in a granule lumen. This is a topological impossibility, not a marginal over-annotation, and ACTR10 is the only dynactin subunit that carries this term. Supporting Evidence: file:human/ACTR10/ACTR10-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton file:human/ACTR10/ACTR10-bioinformatics/RESULTS.md - canonical subunits annotated to GO:0035578 azurophil granule lumen: 1/11 (ACTR10) file:human/ACTR10/ACTR10-uniprot.txt FT CHAIN 1..417 |
| GO:1904813 ficolin-1-rich granule lumen | TAS Reactome:R-HSA-6800434 | REMOVE | Summary: Same granule-lumen assignment for the ficolin-1-rich (specific) granule subset. Identical objection: no secretory-pathway targeting information in the sequence, a single cytoplasmic UniProt location, obligatory residence in a large cytosolic complex, and no canonical dynactin subunit shares the term - the only other dynactin-associated protein that carries it is ACTR1B, the beta-centractin paralog outside the canonical 11. ACTR1B and CAPZA1 are alike in having large non-dynactin pools, but only ACTR1B is on this Reactome route: CAPZA1's single extracellular-region TAS comes from an unrelated S100B/AGER reaction. Reason: Proteomics-derived misassignment to a secretory granule lumen for a cytosolic dynactin subunit. Supporting Evidence: file:human/ACTR10/ACTR10-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton |
| GO:0005524 ATP binding | ISS PMID:36071160 Structure of dynein-dynactin on microtubules shows tandem ad... | NEW | Summary: Proposed new annotation, and the mirror image of the over-annotation this family usually attracts. GOA gives ACTR10 no nucleotide-binding term at all, yet the actin nucleotide site is retained and occupied. Eckley et al. predicted from sequence in 1999 that the actin fold's nucleotide and metal binding elements are conserved in Arp11, and the structures bear it out: a nucleotide is modelled in the Arp11 chain in 19 of the 24 deposited PDB entries that contain ACTR10, and the methods of the 3.37 A pointed-end structure state that ATP-Mg was built into Arp11 on the basis of density while ADP-Mg was built into beta-actin and the Arp1 subunits of the same filament. Computing contacts from the 7Z8M coordinates gives 18 Arp11 residues within 4 A of that ATP, arranged canonically for the actin fold, and 17 of the 18 are identical in human ACTR10; none of beta-actin's own nucleotide contacts fall in an alignment gap. The evidence is ISS rather than IDA because every structure with a modelled nucleotide in this chain is pig ACTR10 (I3LHK5); the two human dynactin structures (9B7J, 9B85) model ADP on the Arp1 chains and AMP-PNP on beta-actin but leave the ACTR10 chain empty. Reason: A concrete annotation gap supported by observed ligand density in the ortholog plus near-complete pig-to-human identity across the contacting residues - 17 of 18, which is orthology rather than conservation relative to actin, where only 9 of 17 of beta-actin's own contacts are shared - and not by fold or family inference. It should be read as a structural/architectural nucleotide site of the kind actin-fold proteins carry: no ATP hydrolysis, exchange or dependence has been assayed for ACTR10, so no ATPase or ATP-dependent-activity term is warranted, and this row deliberately claims binding only. A fourth ground comes from the sibling review of ACTR1A, which proposes GO:0043531 ADP binding for Arp1 on the stated principle of annotating "the term for the ligand actually observed" because no structure has resolved an ATP-bound Arp1. Applied to Arp11 that same principle selects GO:0005524: a structure does resolve ATP in the Arp11 chain, and its authors say so contrastively against the ADP they built into Arp1 and beta-actin. The two reviews therefore differ in term only because the observed ligands differ, not in method. On the choice of term: the ligand modelled in the Arp11 chain is ADP in 14 entries and ATP in 5, so GO:0005524 is not the majority observation and needs a reason. Three things settle it. First, the ATP assignments are the documented ones - the only entry whose text states how the density was interpreted is the 3.37 A pointed-end model, which says ATP-Mg was built into Arp11 while ADP-Mg went into beta-actin and Arp1, so the ATP call is deliberate and contrastive rather than a default. Second, GO's own precedent on the actin fold uses this term: of a 12-member actin/Arp panel only two carry any term under GO:0000166, and both use GO:0005524 - human ACTA1 (TAS, alongside GO:0043531 ADP binding) and yeast ACT1 (IDA). Third, the same survey shows the gap is family-wide rather than a judgement about ACTR10: 10 of 12 members carry no nucleotide-binding term at all, including ACTB, ACTG1 and ACTR1A. A curator preferring to encode the majority state should add GO:0043531 ADP binding as well, exactly as ACTA1 has both; a curator wanting to stay agnostic could use the shared parent GO:0032559 adenyl ribonucleotide binding. Either is defensible, and none of them licenses an ATPase or ATP-dependent-activity term. Supporting Evidence: PMID:36071160 Based on our density, ATP-Mg was built into Arp11 and ADP-Mg was built into PMID:10525537 a primordial core structure that contains nucleotide and metal binding elements PMID:42439233 While actin is defined by its ability to form dynamic filaments, bind and hydrolyze ATP, and serve as a major cytoskeletal scaffold, Arps and actin-like proteins have evolved specialized roles in cytoplasmic and nuclear protein complexes. file:human/ACTR10/ACTR10-bioinformatics/RESULTS.md 17/18 of the pig Arp11 ATP-contacting residues are identical in human ACTR10. file:human/ACTR10/ACTR10-bioinformatics/RESULTS.md Split by ligand modelled in the Arp11 chain: ADP in 14 entries; ATP in 5 entries file:human/ACTR10/ACTR10-bioinformatics/RESULTS.md - 10/12 carry none (ACTB, ACTG1, ACTR1A, ACTR1B, ACTR2, ACTR3, ACTR10, ARP10, ACTL6A, ACTR8) file:human/ACTR10/ACTR10-bioinformatics/RESULTS.md - `GO:0005524` ATP binding: ACTA1, ACT1 file:human/ACTR10/ACTR10-bioinformatics/RESULTS.md 9/17 of beta-actin's own ADP-contacting residues are identical in human ACTR10; 0/17 fall in an alignment gap. file:human/ACTR10/ACTR10-bioinformatics/RESULTS.md Entries in which a nucleotide is modelled in the Arp11 chain: 5AFU (ADP), 6F1T (ADP), 6F38 (ADP), 6F3A (ADP), 6ZNL (ADP), 6ZNM (ADP), 6ZNN (ADP), 6ZNO (ADP), 6ZO4 (ADP), 7Z8F (ATP), 7Z8M (ATP), 8PR4 (ATP), 8PTK (ATP), 9DGS (ADP), 9DGT (ADP), 9DGU (ADP), 9DGV (ADP), 9HHL (ATP), 9YNG (ADP) |
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Download this section (compressed HTML)Q: Does ACTR10's nucleotide site do anything beyond stabilising the fold? ATP-Mg or ADP is modelled in the Arp11 chain of 19 of 24 dynactin structures, and 17 of the 18 ATP-contacting residues are conserved between pig and human, yet no exchange or hydrolysis assay on Arp11 has ever been published. If the site turned over, it would make capping potentially regulated rather than constitutive.
Suggested experts: Andrew P. Carter, Trina A. Schroer
Q: Does ACTR10 bind mitochondria directly, and through what? The zebrafish separation-of-function construct lacking the dynactin-binding region still binds mitochondria, which implies a distinct mitochondrial-facing surface, but no outer-membrane partner has been identified and the result has not been reproduced in a human system.
Suggested experts: Catherine M. Drerup
Q: How is the cargo-selective zebrafish phenotype compatible with ACTR10 being required for dynactin integrity? RNAi in Cos7 cells leaves under a tenth of dynactin assembled when Arp11 is depleted, whereas the zebrafish actr10 mutant shows a mitochondria-restricted retrograde defect. Either the fish allele is hypomorphic for the structural role or vertebrate dynactin tolerates partial Arp11 loss better than Cos7 dynactin, and the two possibilities imply very different annotations.
Suggested experts: Trina A. Schroer, Catherine M. Drerup
Q: Should pan-dynactin biological processes be propagated to individual structural subunits? Reactome records ACTR10 as a participant in MHC class II transport, COPI anterograde transport and COPI-independent Golgi-to-ER retrograde traffic, but only a cytosol location has reached GO from those reactions. A consistent policy would either add the process terms to every subunit or keep them at the complex level and rely on part_of dynactin complex.
Q: Why does ACTR10 appear at focal adhesions and in sperm structures in antibody-based imaging? Human Protein Atlas immunofluorescence lists vesicles, plasma membrane, focal adhesion sites, perinuclear theca and flagellar structures for ACTR10, none of which is expected for a dynactin subunit. Either dynactin has unrecognised localisations or the antibodies cross-react with other actin-fold proteins.
Experiment: Express and purify recombinant human ACTR10 alone and as the ACTR10-DCTN4-DCTN5-DCTN6 pointed-end module, and measure nucleotide occupancy and exchange directly, using HPLC quantification of released nucleotide after denaturation together with fluorescent nucleotide analogue (mant-ATP/mant-ADP) titration and stopped-flow exchange kinetics. In parallel mutate the contact residues identified from the 7Z8M coordinates in the phosphate-binding loops (G21/E22/A23/F24/K26 and G307/G308/T309) and test whether nucleotide-free ACTR10 still assembles into dynactin and still terminates an Arp1 filament in a reconstituted assembly assay. Actin and Arp1 are the natural positive controls, both being nucleotide-loaded in the same structures.
Hypothesis: ACTR10 binds ATP or ADP with a measurable affinity and the bound nucleotide is required for it to cap the Arp1 minifilament.
Type: In vitro nucleotide binding and structure-guided mutagenesis
Experiment: Perform proximity-dependent biotinylation (TurboID or split-TurboID) from endogenously tagged human ACTR10 in a neuronal model such as differentiated iPSC-derived neurons, comparing full-length ACTR10 with the construct region shown in zebrafish to retain mitochondrial binding while lacking the dynactin-binding region. Filter hits against a matched DCTN4 and ACTR1A bait set so that generic dynactin proximity is subtracted, then validate candidate outer-membrane partners by co-immunoprecipitation and by testing whether their depletion phenocopies the ACTR10-dependent retrograde mitochondrial defect in live-cell axonal transport imaging.
Hypothesis: ACTR10 contacts a mitochondrial outer-membrane protein through a surface distinct from its dynactin-binding face.
Type: Proximity labelling proteomics with separation-of-function constructs
Experiment: Fractionate primary human neutrophils into azurophil, specific and gelatinase granules, secretory vesicles, cytosol and membrane, and immunoblot each fraction for ACTR10 alongside all other dynactin subunits and a panel of markers (myeloperoxidase for azurophil granules, ficolin-1 for specific granules, and a soluble cytosolic marker). Protease-protection of intact granules distinguishes lumenal residence from surface association. The prediction is that ACTR10 tracks quantitatively with the cytosolic marker and with the other dynactin subunits and is protease-accessible, which would settle the four removed localisation annotations experimentally.
Hypothesis: Human ACTR10 is not present in neutrophil granules or the extracellular space, and the Reactome-derived annotations reflect cytosolic carryover in granule fractions.
Type: Subcellular fractionation with protease protection and immunoblotting
Experiment: Extend the human dynactin cryo-EM work by focused refinement on the pointed end, using a pointed-end-directed adaptor or the Chlamydia Dre1 handle to improve orientation sampling, and push the ACTR10 chain past 3 A. This would convert the dynactin-complex annotation for human ACTR10 from IBA to IDA and would test directly whether the nucleotide density seen in pig Arp11 is present in the human protein, which is the one point on which the proposed ATP-binding annotation currently depends on the ortholog.
Hypothesis: Human ACTR10 caps the pointed end of human dynactin with a nucleotide bound, and the human structural evidence for both can be obtained at sufficient resolution.
Type: Focused cryo-EM refinement of human dynactin's pointed end
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