AP5Z1 encodes the zeta large subunit of adaptor protein complex 5 (AP-5), a clathrin-independent sorting assembly associated with late endosomes and lysosomes. AP-5 cooperates with SPG11 and ZFYVE26/SPG15 in membrane organization and retrieval of selected cargo toward the Golgi. AP5Z1 supplies part of the structural assembly rather than an established autonomous cargo-binding or helicase activity. Loss of AP5Z1 disrupts endolysosomal morphology and causes hereditary spastic paraplegia 48. Nuclear pools and an experimentally supported homologous-recombination phenotype have also been reported, but their relationship to membrane trafficking remains unresolved.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000724 double-strand break repair via homologous recombination | IMP PMID:20613862 A genome-scale DNA repair RNAi screen identifies SPG48 as a ... | KEEP AS NON CORE | Summary: A reproducible homologous-recombination phenotype is retained outside the trafficking core. Reason: The original two independent esiRNAs impaired human-cell DR-GFP repair and a mouse-orthologue BAC rescued the phenotype. The later AP-5 study explicitly regarded these data as robust while suggesting an indirect explanation. Neither study measured helicase catalysis or established AP5Z1 as a direct DNA-repair machine; uncertainty about mechanism does not negate the source IMP. Supporting Evidence: PMID:20613862 Stable expression of mouse KIAA0415 in the human DR-GFP cell line rendered this cell line resistant to the human esiRNAs, authenticating a role of KIAA0415 in HR-DSBR PMID:22022230 The DNA repair phenotype appears to be robust and on-target, because the authors were able to rescue it with RNAi-resistant KIAA0415. However, the phenotype could be indirect. |
| GO:0005515 protein binding | IPI PMID:20613862 A genome-scale DNA repair RNAi screen identifies SPG48 as a ... | MODIFY | Summary: The AP5B1 association forms part of the structural AP-5 assembly. Reason: The original 2010 affinity-isolation study reports the AP5B1 coassociation with AP5Z1. Its human-cell host does not resolve the species of every tagged BAC reagent; these experiments are not isolated-interface measurements. Explicitly separate human-cell assembly and endogenous-target evidence in PMID:23825025, together with the bounded mouse-zeta structural interface in PMID:40175557, supports AP5Z1 as a structural component of AP-5. GO:0005198 captures this structural role more usefully than generic binding; it does not claim that each original assay measured structural activity or that AP5Z1 recognizes cargo autonomously. Coalesce these replacement assertions downstream while retaining every original partner, reference and evidence code. Proposed replacements: structural molecule activity Supporting Evidence: PMID:20613862 Immunoprecipitation experiments followed by spectrometric identification of co-isolated proteins revealed interactions of KIAA0415-LAP with SPG11, SPG15, C20orf29, and DKFZp761E198 PMID:23825025 Here we show that the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15, both from cytosol and from detergent-extracted membranes, with a stoichiometry of βΌ1:1:1:1:1:1. PMID:40175557 the N-terminal region of SPG11 is required for AP5 complex interaction and assembly. file:human/AP5Z1/AP5Z1-notes.md |
| GO:0005515 protein binding | IPI PMID:20613862 A genome-scale DNA repair RNAi screen identifies SPG48 as a ... | MODIFY | Summary: The ZFYVE26/SPG15 association forms part of the structural AP-5 assembly. Reason: The original 2010 affinity-isolation study reports the ZFYVE26/SPG15 coassociation with AP5Z1. Its human-cell host does not resolve the species of every tagged BAC reagent; these experiments are not isolated-interface measurements. Explicitly separate human-cell assembly and endogenous-target evidence in PMID:23825025, together with the bounded mouse-zeta structural interface in PMID:40175557, supports AP5Z1 as a structural component of AP-5. GO:0005198 captures this structural role more usefully than generic binding; it does not claim that each original assay measured structural activity or that AP5Z1 recognizes cargo autonomously. Coalesce these replacement assertions downstream while retaining every original partner, reference and evidence code. Proposed replacements: structural molecule activity Supporting Evidence: PMID:20613862 Immunoprecipitation experiments followed by spectrometric identification of co-isolated proteins revealed interactions of KIAA0415-LAP with SPG11, SPG15, C20orf29, and DKFZp761E198 PMID:23825025 Here we show that the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15, both from cytosol and from detergent-extracted membranes, with a stoichiometry of βΌ1:1:1:1:1:1. PMID:40175557 the N-terminal region of SPG11 is required for AP5 complex interaction and assembly. file:human/AP5Z1/AP5Z1-notes.md |
| GO:0005515 protein binding | IPI PMID:20613862 A genome-scale DNA repair RNAi screen identifies SPG48 as a ... | MODIFY | Summary: The SPG11 association forms part of the structural AP-5 assembly. Reason: The original 2010 affinity-isolation study reports the SPG11 coassociation with AP5Z1. Its human-cell host does not resolve the species of every tagged BAC reagent; these experiments are not isolated-interface measurements. Explicitly separate human-cell assembly and endogenous-target evidence in PMID:23825025, together with the bounded mouse-zeta structural interface in PMID:40175557, supports AP5Z1 as a structural component of AP-5. GO:0005198 captures this structural role more usefully than generic binding; it does not claim that each original assay measured structural activity or that AP5Z1 recognizes cargo autonomously. Coalesce these replacement assertions downstream while retaining every original partner, reference and evidence code. Proposed replacements: structural molecule activity Supporting Evidence: PMID:20613862 Immunoprecipitation experiments followed by spectrometric identification of co-isolated proteins revealed interactions of KIAA0415-LAP with SPG11, SPG15, C20orf29, and DKFZp761E198 PMID:23825025 Here we show that the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15, both from cytosol and from detergent-extracted membranes, with a stoichiometry of βΌ1:1:1:1:1:1. PMID:40175557 the N-terminal region of SPG11 is required for AP5 complex interaction and assembly. file:human/AP5Z1/AP5Z1-notes.md |
| GO:0005515 protein binding | IPI PMID:20613862 A genome-scale DNA repair RNAi screen identifies SPG48 as a ... | MODIFY | Summary: The AP5S1 association forms part of the structural AP-5 assembly. Reason: The original 2010 affinity-isolation study reports the AP5S1 coassociation with AP5Z1. Its human-cell host does not resolve the species of every tagged BAC reagent; these experiments are not isolated-interface measurements. Explicitly separate human-cell assembly and endogenous-target evidence in PMID:23825025, together with the bounded mouse-zeta structural interface in PMID:40175557, supports AP5Z1 as a structural component of AP-5. GO:0005198 captures this structural role more usefully than generic binding; it does not claim that each original assay measured structural activity or that AP5Z1 recognizes cargo autonomously. Coalesce these replacement assertions downstream while retaining every original partner, reference and evidence code. Proposed replacements: structural molecule activity Supporting Evidence: PMID:20613862 Immunoprecipitation experiments followed by spectrometric identification of co-isolated proteins revealed interactions of KIAA0415-LAP with SPG11, SPG15, C20orf29, and DKFZp761E198 PMID:23825025 Here we show that the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15, both from cytosol and from detergent-extracted membranes, with a stoichiometry of βΌ1:1:1:1:1:1. PMID:40175557 the N-terminal region of SPG11 is required for AP5 complex interaction and assembly. file:human/AP5Z1/AP5Z1-notes.md |
| GO:0005515 protein binding | IPI PMID:23825025 Interaction between AP-5 and the hereditary spastic parapleg... | MODIFY | Summary: The ZFYVE26/SPG15 association forms part of the structural AP-5 assembly. Reason: The original 2013 study identifies a stable AP5Z1-containing assembly with ZFYVE26/SPG15 by quantitative isolation and stoichiometry. This supports coassembly rather than purified binary binding. Explicitly separate human-cell assembly and endogenous-target evidence in PMID:23825025, together with the bounded mouse-zeta structural interface in PMID:40175557, supports AP5Z1 as a structural component of AP-5. GO:0005198 captures this structural role more usefully than generic binding; it does not claim that each original assay measured structural activity or that AP5Z1 recognizes cargo autonomously. Coalesce these replacement assertions downstream while retaining every original partner, reference and evidence code. Proposed replacements: structural molecule activity Supporting Evidence: PMID:23825025 Here we show that the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15, both from cytosol and from detergent-extracted membranes, with a stoichiometry of βΌ1:1:1:1:1:1. file:human/AP5Z1/AP5Z1-notes.md PMID:40175557 the N-terminal region of SPG11 is required for AP5 complex interaction and assembly. |
| GO:0005515 protein binding | IPI PMID:23825025 Interaction between AP-5 and the hereditary spastic parapleg... | MODIFY | Summary: The SPG11 association forms part of the structural AP-5 assembly. Reason: The original 2013 study identifies a stable AP5Z1-containing assembly with SPG11 by quantitative isolation and stoichiometry. This supports coassembly rather than purified binary binding. Explicitly separate human-cell assembly and endogenous-target evidence in PMID:23825025, together with the bounded mouse-zeta structural interface in PMID:40175557, supports AP5Z1 as a structural component of AP-5. GO:0005198 captures this structural role more usefully than generic binding; it does not claim that each original assay measured structural activity or that AP5Z1 recognizes cargo autonomously. Coalesce these replacement assertions downstream while retaining every original partner, reference and evidence code. Proposed replacements: structural molecule activity Supporting Evidence: PMID:23825025 Here we show that the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15, both from cytosol and from detergent-extracted membranes, with a stoichiometry of βΌ1:1:1:1:1:1. file:human/AP5Z1/AP5Z1-notes.md PMID:40175557 the N-terminal region of SPG11 is required for AP5 complex interaction and assembly. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | UNDECIDED | Summary: The HuRI NUP93 pair remains source-specifically unresolved. Reason: Q8N1F7 is NUP93. The publication describes a human binary-interaction resource, but the relevant pair-level experimental table and construct/control details have not been adjudicated. Neither absence from narrative text nor different predominant cellular compartments refutes this interaction. No specific mechanistic refinement or experimental removal is justified. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: The SPG11 association is independently established despite the uninspected screen-level pair data. Reason: The BioPlex publication provides the original screen citation, but its exact AP5Z1-SPG11 experiment remains unadjudicated. Independently inspected 2010 and 2013 immunoprecipitation studies directly establish this biological partnership. Retain the generic interaction as non-core using those explicitly separate corroborating sources; do not attribute their targeted results to the screen or infer an isolated interface from it. Supporting Evidence: PMID:20613862 Immunoprecipitation experiments followed by spectrometric identification of co-isolated proteins revealed interactions of KIAA0415-LAP with SPG11, SPG15, C20orf29, and DKFZp761E198 PMID:23825025 Here we show that the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15, both from cytosol and from detergent-extracted membranes, with a stoichiometry of βΌ1:1:1:1:1:1. |
| GO:0005634 nucleus | IDA PMID:20613862 A genome-scale DNA repair RNAi screen identifies SPG48 as a ... | KEEP AS NON CORE | Summary: Nuclear localization was observed in the source study. Reason: Tagged KIAA0415/AP5Z1 fractionation and imaging in the original source show nuclear and cytoplasmic pools. Two electrophoretic species were discussed as possible isoforms, with the shorter band predominantly nuclear. These bands were not resolved to the current three UniProt isoform accessions. Retain the positive location without treating nuclear residence as the principal membrane-traffic function. Supporting Evidence: PMID:20613862 Cell fractionations showed that the shorter isoform was predominantly nuclear, whereas the longer form was found mostly in the cytoplasm |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: The electronic nuclear-location mapping has independent experimental support. Reason: The UniProt subcellular-location mapping agrees with the original nuclear pool. Preserve the electronic provenance and the unresolved relationship between electrophoretic species and current isoform accessions. Nuclear residence does not establish direct repair activity. Supporting Evidence: PMID:20613862 Cell fractionations showed that the shorter isoform was predominantly nuclear, whereas the longer form was found mostly in the cytoplasm |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Current HPA text supports a nucleoplasmic pool. Reason: The official HPA AP5Z1 subcellular page lists supported nucleoplasm localization, including A-431 antibody staining. This is text-level localization metadata rather than a new image-pixel or antibody-validation analysis. Preserve the source IDA and keep this location outside the main endolysosomal complex core. Supporting Evidence: file:human/AP5Z1/AP5Z1-notes.md |
| GO:0005737 cytoplasm | IDA PMID:20613862 A genome-scale DNA repair RNAi screen identifies SPG48 as a ... | ACCEPT | Summary: A cytoplasmic AP5Z1 pool is directly supported. Reason: The source fractionation and imaging establish a cytoplasmic pool, especially the longer observed protein species. Independent human AP-5 complex studies show cytosolic and membrane-associated complexes. This is consistent with a peripheral sorting adaptor and does not assert a transmembrane topology. Supporting Evidence: PMID:20613862 Cell fractionations showed that the shorter isoform was predominantly nuclear, whereas the longer form was found mostly in the cytoplasm PMID:23825025 Here we show that the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15, both from cytosol and from detergent-extracted membranes, with a stoichiometry of βΌ1:1:1:1:1:1. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: The cytoplasmic mapping agrees with the trafficking protein localization. Reason: The mapped UniProt location agrees with original cytoplasmic fractionation/imaging and the independent cytosolic AP-5 complex. Keep the broad location; neither the original source nor this mapping establishes exclusive cytoplasmic residence. Supporting Evidence: PMID:20613862 Cell fractionations showed that the shorter isoform was predominantly nuclear, whereas the longer form was found mostly in the cytoplasm PMID:23825025 Here we show that the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15, both from cytosol and from detergent-extracted membranes, with a stoichiometry of βΌ1:1:1:1:1:1. |
| GO:0005764 lysosome | NAS PMID:40175557 Structural basis for membrane remodeling by the AP5-SPG11-SP... | ACCEPT | Summary: A lysosome-associated AP5Z1 pool is supported by independent human-cell evidence. Reason: Endogenous human AP5Z1 puncta overlap LAMP1 in control fibroblasts and disappear in AP5Z1-mutant cells in PMID:26085577. The 2013 complex-localization study corroborates this endolysosomal pool. These independent observations support the original broad NAS location; they do not imply an intraluminal protein or make the mouse-zeta structural assembly in PMID:40175557 a human localization assay. Supporting Evidence: PMID:26085577 Note that in control cells there is a significant overlap between LAMP1 and AP-5 ΞΆ. file:human/AP5Z1/AP5Z1-notes.md |
| GO:0005770 late endosome | NAS PMID:22022230 The fifth adaptor protein complex. | ACCEPT | Summary: AP5Z1 belongs to late-endosomal sorting machinery. Reason: The 2011 direct localization panels primarily label ΞΌ5/Ο5, so they establish the complex compartment rather than a ΞΆ-specific tagged assay. AP5Z1 is experimentally part of that complex. Independent 2013 endogenous ΞΆ imaging and 2015 human-cell studies support the late-endosomal/lysosomal pool; the broad NAS is sound without falsely attributing those ΞΆ experiments to the 2011 panels. Supporting Evidence: PMID:26085577 Note that in control cells there is a significant overlap between LAMP1 and AP-5 ΞΆ. PMID:23825025 Here we show that the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15, both from cytosol and from detergent-extracted membranes, with a stoichiometry of βΌ1:1:1:1:1:1. file:human/AP5Z1/AP5Z1-notes.md |
| GO:0005770 late endosome | NAS PMID:40175557 Structural basis for membrane remodeling by the AP5-SPG11-SP... | ACCEPT | Summary: The late-endosomal complex localization is independently corroborated. Reason: Earlier human-cell AP-5 assembly and endogenous AP5Z1 imaging support a late-endosomal/lysosomal pool. They independently corroborate the broad NAS location in the 2025 complex study. The mouse AP5Z1 structural chain is kept distinct from these human observations. Supporting Evidence: PMID:26085577 Note that in control cells there is a significant overlap between LAMP1 and AP-5 ΞΆ. file:human/AP5Z1/AP5Z1-notes.md |
| GO:0007040 lysosome organization | NAS PMID:40175557 Structural basis for membrane remodeling by the AP5-SPG11-SP... | ACCEPT | Summary: AP5Z1 contributes to maintaining lysosomal organization. Reason: AP5Z1 contributes structural machinery for endolysosomal sorting. Human AP5Z1-deficient fibroblasts and AP5Z1-depleted HeLa cells accumulate abnormal multilamellar endolysosomes, supporting the existing lysosome-organization annotation. The later assembled-complex membrane-remodeling work is corroborating context, not an isolated AP5Z1 remodeling assay. Supporting Evidence: PMID:26085577 Note that the loss of AP-5 ΞΆ led to the accumulation of enlarged morphologically defined endosomal structures filled with aberrant storage material, typically containing bands of striated material, multiple exaggerated membrane whorls and many intraluminal vesicles. PMID:40175557 Our findings reveal that the AP5-SPG11-SPG15 complex can bind PI3P molecules, sense membrane curvature and drive membrane remodeling in vitro. file:human/AP5Z1/AP5Z1-notes.md |
| GO:0016192 vesicle-mediated transport | NAS PMID:22022230 The fifth adaptor protein complex. | MODIFY | Summary: Endosomal transport is more specific than general vesicle-mediated transport. Reason: The original AP5Z1 knockdown perturbs the endosomal CIMPR/Vps26 compartment; later human AP5Z1 knockout experiments impair retrieval of CIMPR and selected Golgi cargo toward the Golgi region. Refine the broad NAS to endosomal transport, which is already directly represented for this gene. Do not assign a new narrowly defined transport route from localization alone. This is a merge into the existing supported target term, retaining this source provenance rather than creating a duplicate annotation. Proposed replacements: endosomal transport Supporting Evidence: PMID:22022230 Knockdown of either KIAA0415/SPG48 or C20orf29 phenocopies ΞΌ5 and Ξ²5 knockdowns, causing both the CIMPR and Vps26 to localise to larger puncta. PMID:29381698 Both AP-5 ΞΆ and CIMPR are specifically brought down with SPG15-GFP. |
| GO:0016197 endosomal transport | IMP PMID:22022230 The fifth adaptor protein complex. | ACCEPT | Summary: The original AP5Z1 perturbation supports endosomal transport. Reason: Depleting KIAA0415/AP5Z1 in human HeLa cells alters the CIMPR-positive endosomal compartment, including effects with individual siRNAs. The gene product is an assembled component of sorting machinery rather than transported cargo. Independent 2018 AP5Z1 knockout/retrieval assays strengthen the role while preserving the original IMP and avoiding a claim that ΞΆ directly binds every affected cargo. Supporting Evidence: PMID:22022230 Knockdown of either KIAA0415/SPG48 or C20orf29 phenocopies ΞΌ5 and Ξ²5 knockdowns, causing both the CIMPR and Vps26 to localise to larger puncta. PMID:29381698 Both AP-5 ΞΆ and CIMPR are specifically brought down with SPG15-GFP. |
| GO:0016607 nuclear speck | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA supports nuclear-speckle localization in tested cells. Reason: The official HPA AP5Z1 page records supported nuclear-speckle staining in U-251MG and U2OS. Preserve the source IDA as a secondary observed pool. The current text metadata do not resolve isoforms or establish a nuclear-speckle molecular function. Supporting Evidence: file:human/AP5Z1/AP5Z1-notes.md |
| GO:0030119 AP-type membrane coat adaptor complex | NAS PMID:22022230 The fifth adaptor protein complex. | MODIFY | Summary: The specific AP-5 complex term is available. Reason: The original study identifies KIAA0415 as the ΞΆ large subunit of AP-5 with AP5B1, AP5M1 and AP5S1. GO0044599 is an AP-type membrane coat adaptor complex child and directly captures this experimentally established assembly. This refinement does not imply AP-5 binds clathrin. This is a merge into the existing supported target term, retaining this source provenance rather than creating a duplicate annotation. Proposed replacements: AP-5 adaptor complex Supporting Evidence: PMID:23825025 Here we show that the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15, both from cytosol and from detergent-extracted membranes, with a stoichiometry of βΌ1:1:1:1:1:1. |
| GO:0044599 AP-5 adaptor complex | IEA GO_REF:0000002 | ACCEPT | Summary: The InterPro-derived AP-5 membership is supported by direct assembly studies. Reason: IPR028222 identifies the AP5Z1 family, and independent actual subunit coassembly and complex characterization support AP-5 membership. The domain mapping is not being used as proof of a helicase or clathrin-binding activity. Supporting Evidence: PMID:23825025 Here we show that the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15, both from cytosol and from detergent-extracted membranes, with a stoichiometry of βΌ1:1:1:1:1:1. |
| GO:0044599 AP-5 adaptor complex | NAS PMID:22022230 The fifth adaptor protein complex. | ACCEPT | Summary: AP5Z1 is the ΞΆ subunit of AP-5. Reason: The original study identifies the fourth AP-5 subunit using structural homology, coassociation and matched trafficking perturbations. Independent quantitative isolation of all four subunits with SPG11/SPG15 corroborates the specific complex. Retain the original NAS rather than converting its evidence code to that of later assays. Supporting Evidence: PMID:23825025 Here we show that the four AP-5 subunits can be coimmunoprecipitated with SPG11 and SPG15, both from cytosol and from detergent-extracted membranes, with a stoichiometry of βΌ1:1:1:1:1:1. |
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Download this section (compressed HTML)Q: Does the AP-5βSPG11βSPG15 assembly directly bridge cargo receptors, membrane and a vesicle-coat scaffold as required by GO:0140312, and which subunit surfaces perform those contacts?
Q: How does AP5Z1 perturbation influence homologous recombination, and is the effect separable from trafficking-dependent signaling?
Q: Which present-day AP5Z1 alternative products account for the reported nuclear and cytoplasmic protein species?
Q: Does the AP5Z1βNUP93 HuRI pair reproduce with endogenous proteins and defined constructs?
Experiment: Reconstitute defined human AP-5βSPG11βSPG15 complexes with cargo receptors and separation-of-function zeta interface mutants, measuring cargo association and membrane remodeling independently.
Experiment: Compare repair and endosomal-retrieval rescue by isoform-resolved AP5Z1 constructs expressed at matched abundance to separate nuclear and trafficking mechanisms.
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