AIPL1 is a retina- and pineal-enriched co-chaperone that supports the folding, assembly and stability of photoreceptor phosphodiesterase 6 (PDE6). Its TPR region and intact domain organization mediate association with HSP90, while its FKBP-like domain recognizes prenyl groups on client proteins. These complementary interactions support PDE6 biogenesis in the photoreceptor cytoplasm and inner segment. Nuclear AIPL1 is also detected during human retinal development. Biallelic loss of AIPL1 compromises PDE6 abundance and cGMP homeostasis and causes severe early-onset retinal degeneration, including Leber congenital amaurosis 4.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003755 peptidyl-prolyl cis-trans isomerase activity | IEA GO_REF:0000002 | REMOVE | Summary: The FKBP-like fold does not confer peptidyl-prolyl isomerase activity on AIPL1. Reason: GOA maps InterPro:IPR046357 to a catalytic PPIase term. Gene-specific biochemical literature describes the AIPL1 FKBP domain as lacking FK506 binding and PPIase activity, while establishing a prenyl-recognition function. PMID:23737531 reports that negative catalytic assessment from earlier work; its own principal experiments concern farnesyl binding. The later mechanistic study PMID:35065964 also identifies AIPL1 as a non-isomerase co-chaperone. Reject this catalytic transfer without disputing the genuine FKBP-like structural domain. Propagation Review Root cause: PROPAGATION BAD Failure modes: PSEUDO OR SUBACTIVITY LOSS Sources checked: InterPro:IPR046357 SOURCE WEAK OR INFERRED This is the GOA-identified PPIase-domain-superfamily mapping source. The fold assignment is compatible with AIPL1, but gene-specific evidence argues against inferring catalytic PPIase activity. The complete InterPro mapping rule was not independently reconstructed. Supporting Evidence: PMID:23737531 Unlike prototypical immunophilin FKBP domains, the FKBP domain of AIPL1 does not bind FK506 or exhibit peptidylprolylisomerase activity |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Human retinal immunohistochemistry supports a developmental nuclear AIPL1 pool. Reason: The UniProt subcellular-location mapping traces to PMID:12374762. The original Figure 6, independently accessible through PubMed, shows AIPL1 in nuclei of differentiating human photoreceptors at fetal weeks 14 and 16. This is positive localization evidence, not an inference from TPR motifs. Retain the nuclear pool as contextual localization; a distinct nuclear molecular activity has not been established by these staining experiments. The compartment-specific evidence is the externally inspected original Results/Figure 6, not the compartment-agnostic abstract in the local cache. The immutable UniProt record additionally lists HPA nuclear-speck/nucleoplasm IDA annotations as database corroboration; these are not new primary assays performed by this review. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0191 SUPPORTS TRANSFER The nuclear-location mapping is backed by the cached UniProt PMID:12374762 attribution and the original human fetal-retina staining in Figure 6. Exact figure content was read externally; the local publication remains abstract-only. Supporting Evidence: file:human/AIPL1/AIPL1-uniprot.txt DR GO; GO:0016607; C:nuclear speck; IDA:HPA. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: AIPL1 operates in the photoreceptor cytoplasm during PDE6 biogenesis. Reason: UniProt maps the cytoplasmic location from PMID:12374762, whose human retinal staining includes photoreceptor inner segments. Human AIPL1 experiments in PMID:28973376 independently support HSP90-dependent stabilization of PDE6Ξ± in the cytosol. The broad cytoplasm term is accurate at this source resolution and encompasses the functional site without implying exclusive localization. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0086 SUPPORTS TRANSFER UniProt explicitly records cytoplasm with experimental PMID:12374762 support; the separate human AIPL1/PDE6 study corroborates the cytosolic functional context. Supporting Evidence: PMID:28973376 These AIPL1 variants moreover failed to promote the HSP90-dependent stabilization of the PDE6Ξ± subunit in the cytosol. |
| GO:0005515 protein binding | IPI PMID:12374762 The inherited blindness associated protein AIPL1 interacts w... | REMOVE | Summary: The AIPL1βNUB1 interaction is supported, but generic protein binding does not specify its function. Reason: PMID:12374762 verifies binding to NUB1 (UniProtKB:Q9Y5A7), including co-immunoprecipitation in human Y79 cells. That interaction is retained as biological evidence. The paper proposes developmental and cell-cycle implications but does not establish a specific molecular activity for the pair. The separate FAT10/PDE6 results in PMID:32817338 do not by themselves assign such an activity to this NUB1 interaction. Remove the uninformative generic binding annotation without claiming that the interaction is false. Supporting Evidence: PMID:12374762 The AIPL1-NUB1 interaction was verified by co-immunoprecipitation studies in Y79 retinoblastoma cells |
| GO:0005515 protein binding | IPI PMID:21044950 Genome-wide YFP fluorescence complementation screen identifi... | REMOVE | Summary: The TINF2 interaction-screen annotation provides no specific AIPL1 molecular function. Reason: The GOA partner is TINF2 (UniProtKB:Q9BSI4), also listed in the cached UniProt interaction record. PMID:21044950 describes a split-YFP complementation screen in human cells. Its cached extraction supplies the abstract and Discussion but not the AIPL1-specific pair-level validation. The generic binding term remains functionally uninformative; remove it without denying the interaction or inferring that AIPL1 cannot act outside photoreceptors. No telomere-specific function is assigned from the screen. Supporting Evidence: PMID:21044950 Of the βΌ12,000 human proteins examined, we identified over 300 proteins that associated with the six core telomeric proteins. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: The HuRI row aggregates binary interactions without establishing a specific AIPL1 activity. Reason: The source GOA tuples name LBX1 (P52954), SMAP1 isoform Q8IYB5-2, PLSCR3 (Q9NRY6) and TXNL4B (Q9NX01), matching the cached UniProt interaction list. PMID:32296183 is a systematic binary-interaction study; its full article does not supply the pair-specific functional interpretation in the cached text. Remove generic protein binding as uninformative, while preserving all reported partners and avoiding a claim that the interactions are false. A chaperone or adaptor activity cannot be inferred for these partners merely from their association. Supporting Evidence: PMID:32296183 the cellular function of most individual PPIs remains to be elucidated |
| GO:0001917 photoreceptor inner segment | IEA GO_REF:0000107 | ACCEPT | Summary: Conserved photoreceptor inner-segment localization is supported by mouse and human staining. Reason: The Ensembl transfer names mouse Aipl1 Q924K1 and ENSMUSP00000036279. The historical MGI comparative graph traces the mouse inner-segment IDA to PMID:14555765; that paper localizes Aipl1 to mouse inner segments. Independent human Figure 6 in PMID:12374762 shows inner-segment staining in child and adult retina. These are direct localization observations supporting the transfer, beyond coherence with the PDE6 chaperone mechanism. Compartment resolution comes from the externally inspected original Figures and Results, not from the broad photoreceptor-expression abstract. The UniProt inner-segment entry is database corroboration, not an independent additional experiment. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q924K1 SUPPORTS TRANSFER Mouse Aipl1; the MGI comparative graph generated 2007-12-07 links inner-segment IDA to PMID:14555765. Independent human PMID:12374762 Figure 6 supports conservation. ensembl:ENSMUSP00000036279 SUPPORTS TRANSFER The mouse Ensembl donor co-occurs with Q924K1 in this GOA transfer. Mouse source staining and independent human retinal staining support the location; no phylogenetic IBA is involved. Supporting Evidence: file:human/AIPL1/AIPL1-uniprot.txt DR GO; GO:0001917; C:photoreceptor inner segment; IEA:Ensembl. |
| GO:0001918 farnesylated protein binding | IDA PMID:14555765 AIPL1, a protein implicated in Leber's congenital amaurosis,... | ACCEPT | Summary: AIPL1 recognizes farnesylated proteins through its FKBP-like domain. Reason: PMID:14555765 uses prenylation-defective substrate mutants and farnesyltransferase-deficient yeast to establish farnesyl-dependent interaction with DNAJA2 and transducin-Ξ³. PMID:23737531 independently maps farnesyl-Cys binding to the FKBP-like domain. This is a supported molecular recognition activity. Later mouse and heterologous PDE6 assays show that prenyl binding is not absolutely required for maturation in those tested systems; that result does not negate the binding activity or establish that it has no physiological contribution. Supporting Evidence: PMID:14555765 The screen demonstrated that AIPL1 interacts specifically with farnesylated proteins. PMID:23737531 farnesylated-Cys binds exclusively to the FKBP domain of AIPL1 |
| GO:0005634 nucleus | IDA PMID:12374762 The inherited blindness associated protein AIPL1 interacts w... | KEEP AS NON CORE | Summary: AIPL1 was detected in nuclei of developing human photoreceptors. Reason: The original PMID:12374762 Figure 6 provides positive nuclear immunohistochemistry at fetal weeks 14 and 16, independently inspected on the primary PubMed record. Retain this experimental localization. Nuclear staining does not identify a nuclear molecular function, so it is kept as developmental cellular context alongside the cytoplasmic PDE6-biogenesis function. The compartment-specific evidence is the externally inspected original Results/Figure 6, not the compartment-agnostic abstract in the local cache. The immutable UniProt record additionally lists HPA nuclear-speck/nucleoplasm IDA annotations as database corroboration; these are not new primary assays performed by this review. Supporting Evidence: file:human/AIPL1/AIPL1-uniprot.txt DR GO; GO:0016607; C:nuclear speck; IDA:HPA. |
| GO:0005737 cytoplasm | IDA PMID:12374762 The inherited blindness associated protein AIPL1 interacts w... | ACCEPT | Summary: The experimental cytoplasmic location agrees with AIPL1-mediated PDE6 biogenesis. Reason: PMID:12374762 is the original curated localization source and its human retinal Figure 6 includes inner-segment staining. The broad cytoplasm annotation is retained at that source resolution. Human AIPL1 work in PMID:28973376 independently links its HSP90 interaction to stabilization of PDE6Ξ± in the cytosol; neither source requires that AIPL1 be exclusively cytoplasmic. Supporting Evidence: PMID:12374762 AIPL1 is present in the developing photoreceptor layer of the human retina and within the photoreceptors of the adult retina PMID:28973376 These AIPL1 variants moreover failed to promote the HSP90-dependent stabilization of the PDE6Ξ± subunit in the cytosol. |
| GO:0018343 protein farnesylation | IDA PMID:14555765 AIPL1, a protein implicated in Leber's congenital amaurosis,... | MODIFY | Summary: The measured client-processing effect supports protein maturation while the precise prenyl-processing step remains unresolved. Reason: The original human-AIPL1/human-DNAJA2 experiment in PMID:14555765 measures a larger processed-client fraction, with a nonprenylatable control and disease-variant comparisons. That is positive evidence for maturation assistance. It does not isolate covalent farnesyl addition from later CAAX proteolysis, methylation, delivery or client protection. Broaden the process to GO:0051604 protein maturation, preserving the original acts_upstream_of_or_within qualifier and IDA provenance. This accepts the measured effect without declaring farnesylation impossible or substituting later PDE6 assays for the original experiment. Independent human AIPL1/PDE6 stabilization and mouse AIPL1 functional-folding studies support the broader maturation role; AIPL1 performs client recognition and co-chaperone work rather than merely being its substrate. Proposed replacements: protein maturation Supporting Evidence: PMID:14555765 Analysis of isoprenylation in cultured human cells shows that AIPL1 enhances the processing of farnesylated proteins. |
| GO:0005634 nucleus | TAS PMID:10615133 Mutations in a new photoreceptor-pineal gene on 17p cause Le... | KEEP AS NON CORE | Summary: Later human retinal staining supports the nuclear location originally inferred from the discovery study. Reason: PMID:10615133 proposes nuclear transport or chaperone activity from the TPR motifs; the accessible abstract does not itself demonstrate a nuclear pool. Independent PMID:12374762 Figure 6 provides human fetal photoreceptor nuclear staining, supporting the location at the gene level. Retain the nuclear annotation as non-core while distinguishing the original sequence-based rationale from the later direct observation. The compartment-specific evidence is the externally inspected original Results/Figure 6, not the compartment-agnostic abstract in the local cache. The immutable UniProt record additionally lists HPA nuclear-speck/nucleoplasm IDA annotations as database corroboration; these are not new primary assays performed by this review. Supporting Evidence: file:human/AIPL1/AIPL1-uniprot.txt DR GO; GO:0016607; C:nuclear speck; IDA:HPA. |
| GO:0007601 visual perception | TAS PMID:10615133 Mutations in a new photoreceptor-pineal gene on 17p cause Le... | KEEP AS NON CORE | Summary: Visual perception is a supported physiological consequence of AIPL1-dependent PDE6 biogenesis. Reason: Retain the curated visual-perception association as a non-core physiological outcome. Human disease genetics and retinal-organoid replacement support its importance for visual function, while the molecular work performed by AIPL1 is client recognition and PDE6 maturation. The protein does not itself detect photons or catalyze the PDE6 signaling reaction; maturation is the direct process synthesized in the core. Supporting Evidence: PMID:10615133 A homozygous nonsense mutation at codon 278 is present in all affected members of the original LCA4 family. PMID:38439910 Notably, the loss of retinal phosphodiesterase 6 was rescued and elevated cyclic guanosine monophosphate (cGMP) levels were reduced following treatment. |
| GO:0051879 Hsp90 protein binding | IPI PMID:28973376 The integrity and organization of the human AIPL1 functional... | NEW | Summary: Human AIPL1 binds HSP90 as a substrate-specific co-chaperone. Reason: Retain the specific Hsp90-binding proposal on human evidence from PMID:28973376: reciprocal co-immunoprecipitation, directed interaction assays and ELISA with human HSP90Ξ±/Ξ² support the interaction and its dependence on AIPL1 domain integrity. The original primary reference for this author-proposed row, PMID:35065964, tests mouse AIPL1 with human HSP90Ξ² and human PDE6C, so it supplies orthologous mechanistic corroboration rather than direct human AIPL1 IDA. The corrected IPI citation makes that provenance explicit. No broader heat-shock-protein binding or redundant generic protein-binding proposal is added. Supporting Evidence: PMID:28973376 Our data revealed that both the FK506 binding protein (FKBP)-like domain and the tetratricopeptide repeat (TPR) domain of AIPL1 are required for interaction with HSP90. PMID:35065964 We investigated interactions of the full-length mouse AIPL1 (aa 1β328) with the apo- and AMPPNP-bound states of HSP90. |
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Download this section (compressed HTML)Q: Which step of DNAJA2 CAAX processing is enhanced by AIPL1: farnesyl transfer, subsequent cleavage/methylation, or retention and trafficking of processed protein? The mobility assay in PMID:14555765 does not distinguish these possibilities.
Q: What kinetic or spatial contribution does prenyl recognition make to PDE6 biogenesis in human photoreceptors, given the preserved endpoint maturation in the mouse and heterologous systems of PMID:35065964?
Q: Does the developmental nuclear AIPL1 pool carry a distinct molecular activity, and how is it related to cytoplasmic co-chaperoning?
Q: Do additional primary HSP70 or NUB1 experiments justify a specific functional annotation beyond the supported HSP90 interaction and contextual FAT10/PDE6 findings?
Q: Would human client-folding assays support GO:0044183 protein folding chaperone, or contribution to a defined chaperone complex, beyond the established HSP90-binding activity? Distinguish active folding assistance from unfolded-protein binding or holdase activity.
Experiment: Measure farnesyl incorporation, terminal peptide cleavage and methylation separately for DNAJA2 with and without AIPL1, alongside the mobility shift and client abundance. Include the nonprenylatable client control and binding-deficient AIPL1 variants.
Hypothesis: AIPL1 changes one or more separable stages of client CAAX processing.
Type: Step-resolved biochemical processing assay
Experiment: Compare human AIPL1 prenyl-binding variants with HSP90-interface variants in retinal organoids, using time-resolved PDE6 assembly, localization and direct cGMP-hydrolysis measurements.
Hypothesis: Prenyl recognition improves the rate or spatial fidelity of PDE6 biogenesis in human photoreceptors without being absolutely required for endpoint folding.
Type: Human retinal-organoid variant complementation
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