id: Q9NZN9 gene_symbol: AIPL1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- AIPL1 is a retina- and pineal-enriched FKBP-like/TPR-domain co-chaperone required for normal photoreceptor function. Its TPR region binds HSP90, while its FKBP-like domain binds prenyl/farnesyl moieties rather than acting as a peptidyl-prolyl isomerase. AIPL1 works with HSP90 to promote maturation and stable assembly of rod and cone phosphodiesterase 6 (PDE6), the cGMP phosphodiesterase that drives phototransduction. Loss of AIPL1 destabilizes PDE6 and causes severe early-onset retinal degeneration, including Leber congenital amaurosis 4. alternative_products: - name: '1' id: Q9NZN9-1 - name: '2' id: Q9NZN9-2 sequence_note: VSP_041507 - name: 3 (AIPL2) id: Q9NZN9-3 sequence_note: VSP_041508 - name: '4' id: Q9NZN9-4 sequence_note: VSP_047708 - name: '5' id: Q9NZN9-5 sequence_note: VSP_047709 existing_annotations: - term: id: GO:0003755 label: peptidyl-prolyl cis-trans isomerase activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: >- This InterPro2GO annotation is based on the FKBP-like/PPIase domain in AIPL1. The domain assignment is structurally correct, but the molecular activity is not supported for AIPL1. The AIPL1 FKBP-like domain has diverged into a farnesyl/prenyl-binding module used in PDE6 chaperone biology, and published biochemical work explicitly states that it does not exhibit PPIase activity. action: REMOVE reason: >- AIPL1 should not be annotated as a peptidyl-prolyl cis-trans isomerase solely from its FKBP-like domain. Gene-specific evidence indicates lack of FK506 binding and lack of peptidylprolylisomerase activity, so the computational FKBP/PPIase transfer is an overcall. additional_reference_ids: - PMID:23737531 supported_by: - reference_id: PMID:23737531 supporting_text: the FKBP domain of AIPL1 does not bind FK506 or exhibit peptidylprolylisomerase activity reference_section_type: DISCUSSION - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: >- This IEA annotation comes from the UniProtKB subcellular-location vocabulary. UniProtKB records AIPL1 as nuclear and cytoplasmic based on PMID:12374762. The cached abstract does not provide the exact subcellular compartment detail, but it does support AIPL1 expression in developing and adult photoreceptors. action: KEEP_AS_NON_CORE reason: >- Retain the UniProt-derived nuclear localization as non-core cellular-location information. AIPL1's core reviewed function is the cytoplasmic/photoreceptor co-chaperone role in PDE6 maturation rather than a nuclear function. additional_reference_ids: - PMID:12374762 - file:human/AIPL1/AIPL1-uniprot.txt - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: >- This IEA annotation comes from the UniProtKB subcellular-location vocabulary. Cytoplasmic localization is consistent with AIPL1's role in the HSP90/AIPL1 chaperone pathway for nascent PDE6 and with UniProtKB's PMID:12374762-backed subcellular-location statement. action: ACCEPT reason: >- Cytoplasmic localization is consistent with the main biochemical function of AIPL1 as an HSP90-associated PDE6 maturation factor. additional_reference_ids: - PMID:12374762 - PMID:35065964 - file:human/AIPL1/AIPL1-uniprot.txt - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:12374762 qualifier: enables review: summary: >- This IPI annotation captures the experimentally verified AIPL1 interaction with NUB1 in Y79 retinoblastoma cells. The interaction is real but not the best representation of AIPL1's core molecular role in photoreceptor PDE6 maturation. action: KEEP_AS_NON_CORE reason: >- Retain the verified NUB1 interaction as non-core protein-binding information. The generic GO:0005515 term is uninformative for core function, and the NUB1 interaction is less directly tied to AIPL1's established HSP90/PDE6 co-chaperone function. Later work nonetheless connects this NUB1/FAT10 axis to PDE6 proteostasis (FAT10 conjugates to PDE6 for proteasomal degradation and AIPL1 stabilizes the FAT10 monomer and PDE6-FAT10 conjugate; PMID:32817338), but this remains a proteostasis-modulation interaction rather than AIPL1's core molecular function. additional_reference_ids: - PMID:32817338 supported_by: - reference_id: PMID:12374762 supporting_text: The AIPL1-NUB1 interaction was verified by co-immunoprecipitation studies in Y79 retinoblastoma cells reference_section_type: ABSTRACT - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21044950 qualifier: enables review: summary: >- This annotation records an AIPL1-TINF2 interaction from a large-scale YFP complementation screen centered on telomere proteins. The study is useful high-throughput interaction evidence, but it does not establish a telomere role or core proteostasis role for AIPL1. action: MARK_AS_OVER_ANNOTATED reason: >- GO:0005515 is too generic, and this high-throughput telomere-interactome result should not drive the functional interpretation of a retina-specific PDE6 co-chaperone. Keep the source interaction available for specialist review, but do not treat it as core AIPL1 biology. supported_by: - reference_id: PMID:21044950 supporting_text: we identified over 300 proteins that associated with the six core telomeric proteins reference_section_type: ABSTRACT - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: >- This annotation represents AIPL1 interactions from the HuRI human binary interactome resource. The publication describes a broad systematic Y2H reference map rather than AIPL1-focused mechanistic work. action: MARK_AS_OVER_ANNOTATED reason: >- The HuRI interactions are useful interaction-screen evidence, but the generic protein-binding term and lack of AIPL1-specific mechanistic follow-up make this unsuitable as a core annotation for AIPL1. supported_by: - reference_id: PMID:32296183 supporting_text: the cellular function of most individual PPIs remains to be elucidated reference_section_type: DISCUSSION - term: id: GO:0001917 label: photoreceptor inner segment evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: >- This Ensembl Compara transfer is consistent with AIPL1 expression in developing and adult human photoreceptors and with its role in the biosynthetic maturation of PDE6, which occurs before delivery of PDE6 to the outer segment. action: ACCEPT reason: >- Accept as a conserved photoreceptor localization annotation. The exact inner segment localization is not the primary molecular function, but it is coherent with AIPL1's photoreceptor-specific PDE6 maturation role. additional_reference_ids: - PMID:12374762 - PMID:35065964 supported_by: - reference_id: PMID:12374762 supporting_text: AIPL1 is present in the developing photoreceptor layer of the human retina and within the photoreceptors of the adult retina reference_section_type: ABSTRACT - term: id: GO:0001918 label: farnesylated protein binding evidence_type: IDA original_reference_id: PMID:14555765 qualifier: enables review: summary: >- This annotation is well supported. AIPL1 was identified as specifically interacting with farnesylated proteins, and later biochemical work showed high-affinity binding of a farnesylated-Cys probe to the FKBP-like domain. action: ACCEPT reason: >- Farnesyl/prenyl binding is a genuine AIPL1 molecular function and explains why the FKBP-like domain should be interpreted as a lipid-binding module rather than as an enzymatic PPIase domain. additional_reference_ids: - PMID:23737531 - PMID:35065964 supported_by: - reference_id: PMID:14555765 supporting_text: AIPL1 interacts specifically with farnesylated proteins reference_section_type: ABSTRACT - reference_id: PMID:23737531 supporting_text: farnesylated-Cys binds exclusively to the FKBP domain of AIPL1 reference_section_type: DISCUSSION - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:12374762 qualifier: located_in review: summary: >- This experimental localization annotation is based on the AIPL1/NUB1 paper. The cached abstract confirms AIPL1 localization was examined in developing and adult retina but does not include the detailed nucleus/cytoplasm wording. action: KEEP_AS_NON_CORE reason: >- Retain as non-core localization information. The review does not identify a nuclear molecular function for AIPL1, and the main curated function is the HSP90/PDE6 co-chaperone role. additional_reference_ids: - file:human/AIPL1/AIPL1-uniprot.txt - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:12374762 qualifier: located_in review: summary: >- This experimental localization annotation is consistent with UniProtKB and with AIPL1's HSP90-associated co-chaperone function in PDE6 maturation. action: ACCEPT reason: >- Cytoplasmic localization is biologically coherent with AIPL1's established role in maturation of nascent PDE6. additional_reference_ids: - PMID:35065964 - file:human/AIPL1/AIPL1-uniprot.txt - term: id: GO:0018343 label: protein farnesylation evidence_type: IDA original_reference_id: PMID:14555765 qualifier: acts_upstream_of_or_within review: summary: >- PMID:14555765 showed that AIPL1 interacts with and aids processing of farnesylated proteins, but AIPL1 is not a farnesyltransferase and the evidence does not show that AIPL1 catalyzes farnesyl addition. More recent work places AIPL1 in HSP90-dependent PDE6 maturation, with farnesyl/prenyl binding as a substrate-tethering feature rather than the farnesylation reaction itself. action: MODIFY reason: >- The biological process should be represented as protein maturation rather than protein farnesylation. AIPL1 acts on already prenylated/farnesylated PDE6 substrates and promotes maturation/assembly of functional PDE6, but does not perform the lipid modification reaction. proposed_replacement_terms: - id: GO:0051604 label: protein maturation additional_reference_ids: - PMID:35065964 supported_by: - reference_id: PMID:14555765 supporting_text: AIPL1 enhances the processing of farnesylated proteins reference_section_type: ABSTRACT - reference_id: PMID:35065964 supporting_text: Disruption of the AIPL1 interaction with HSP90 impedes maturation of PDE6 reference_section_type: RESULTS - term: id: GO:0005634 label: nucleus evidence_type: TAS original_reference_id: PMID:10615133 qualifier: located_in review: summary: >- The TAS nuclear annotation traces to the gene-discovery paper that identified AIPL1 as a photoreceptor/pineal gene with TPR motifs consistent with nuclear transport or chaperone activity. This is weak as evidence for a core nuclear function. action: KEEP_AS_NON_CORE reason: >- Retain only as non-core location-associated information. The strongest current AIPL1 biology is its cytoplasmic HSP90/PDE6 co-chaperone role in photoreceptors. supported_by: - reference_id: PMID:10615133 supporting_text: whose protein contains three tetratricopeptide (TPR) motifs, consistent with nuclear transport or chaperone activity reference_section_type: ABSTRACT - term: id: GO:0007601 label: visual perception evidence_type: TAS original_reference_id: PMID:10615133 qualifier: involved_in review: summary: >- This annotation is supported by the severe early-onset retinal phenotype caused by AIPL1 mutations and by mechanistic work showing that AIPL1 is required for functional maturation of PDE6, a core phototransduction enzyme. action: ACCEPT reason: >- AIPL1 is required for photoreceptor function through HSP90-dependent maturation and stability of PDE6, so visual perception is an appropriate biological-process annotation. additional_reference_ids: - PMID:35065964 - PMID:28973376 supported_by: - reference_id: PMID:10615133 supporting_text: AIPL1 mutations may cause approximately 20% of recessive LCA reference_section_type: ABSTRACT - reference_id: PMID:35065964 supporting_text: Phosphodiesterase 6 (PDE6) is a key effector enzyme in vertebrate phototransduction reference_section_type: ABSTRACT - term: id: GO:0051879 label: Hsp90 protein binding evidence_type: IDA original_reference_id: PMID:35065964 qualifier: enables review: summary: >- NEW annotation recommended for the PN proteostasis review. AIPL1 has direct, gene-specific HSP90-binding evidence from biochemical assays, and HSP90 binding is required for efficient PDE6 maturation. This is a more precise and better supported representation than the projected broad heat shock protein binding term. action: NEW reason: >- AIPL1-specific literature supports HSP90 binding directly. The PN projection to GO:0031072 heat shock protein binding is directionally correct, but direct curation should use GO:0051879 Hsp90 protein binding because the strongest primary evidence is for HSP90. additional_reference_ids: - PMID:28973376 - PMID:29721967 - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv supported_by: - reference_id: PMID:35065964 supporting_text: AIPL1 preferentially binds to HSP90 in the closed state with a stoichiometry of 1:2 reference_section_type: ABSTRACT - reference_id: PMID:28973376 supporting_text: AIPL1 functions as a photoreceptor-specific co-chaperone that interacts with the molecular chaperone HSP90 reference_section_type: ABSTRACT core_functions: - molecular_function: id: GO:0051879 label: Hsp90 protein binding directly_involved_in: - id: GO:0051604 label: protein maturation - id: GO:0007601 label: visual perception locations: - id: GO:0005737 label: cytoplasm - id: GO:0001917 label: photoreceptor inner segment description: >- AIPL1 binds HSP90 through its TPR region and functions as a specialized photoreceptor co-chaperone for PDE6 maturation. HSP90-binding mutants reduce or abolish AIPL1-dependent PDE6 activity in heterologous assays, supporting HSP90 binding as the most defensible PN proteostasis molecular-function annotation for AIPL1. supported_by: - reference_id: PMID:35065964 supporting_text: Disruption of the AIPL1 interaction with HSP90 impedes maturation of PDE6 reference_section_type: RESULTS - reference_id: PMID:28973376 supporting_text: AIPL1 functions as a photoreceptor-specific co-chaperone that interacts with the molecular chaperone HSP90 reference_section_type: ABSTRACT - molecular_function: id: GO:0001918 label: farnesylated protein binding locations: - id: GO:0005737 label: cytoplasm - id: GO:0001917 label: photoreceptor inner segment description: >- AIPL1 binds farnesyl/prenyl moieties through its FKBP-like domain. This lipid binding is a real AIPL1 molecular function, but it should be kept separate from the HSP90-dependent PDE6 maturation core function because prenyl binding is not required for PDE6 maturation in the later mechanistic study. supported_by: - reference_id: PMID:14555765 supporting_text: AIPL1 interacts specifically with farnesylated proteins reference_section_type: ABSTRACT - reference_id: PMID:23737531 supporting_text: farnesylated-Cys binds exclusively to the FKBP domain of AIPL1 reference_section_type: DISCUSSION - reference_id: PMID:35065964 supporting_text: neither sequestration of the prenyl modifications is required for PDE6 maturation to proceed reference_section_type: RESULTS proposed_new_terms: [] suggested_questions: - question: >- Does direct primary evidence support a separate Hsp70 protein binding annotation for AIPL1, or should current GO curation remain limited to HSP90 binding until gene-specific HSP70 assays are reviewed? - question: >- Does AIPL1's stabilization of FAT10 and the PDE6-FAT10 conjugate (PMID:32817338) warrant a distinct biological-process annotation linking AIPL1 to regulation of PDE6 proteasomal turnover, or is it best captured under protein maturation/stability? suggested_experiments: - hypothesis: >- AIPL1-HSP90 binding is the essential proteostasis interaction for PDE6 maturation, whereas farnesyl/prenyl binding modulates substrate handling but is not itself a PPIase activity. description: >- Compare human AIPL1 TPR-interface mutants and FKBP/prenyl-binding mutants in photoreceptor-relevant PDE6 maturation assays, measuring PDE6 abundance, catalytic activity, and rescue of photoreceptor phenotypes. experiment_type: mutational rescue and PDE6 activity assay references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000044 title: >- Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: PMID:10615133 title: Mutations in a new photoreceptor-pineal gene on 17p cause Leber congenital amaurosis. findings: - statement: AIPL1 is a photoreceptor/pineal gene with TPR motifs and LCA-associated mutations. supporting_text: >- We describe here a new photoreceptor/pineal-expressed gene, AIPL1 (encoding aryl-hydrocarbon interacting protein-like 1), that maps within the LCA4 candidate region and whose protein contains three tetratricopeptide (TPR) motifs reference_section_type: ABSTRACT - id: PMID:12374762 title: The inherited blindness associated protein AIPL1 interacts with the cell cycle regulator protein NUB1. findings: - statement: AIPL1 interacts with NUB1 and is present in human photoreceptors. supporting_text: >- The AIPL1-NUB1 interaction was verified by co-immunoprecipitation studies in Y79 retinoblastoma cells reference_section_type: ABSTRACT - statement: AIPL1 is expressed in developing and adult photoreceptors. supporting_text: >- AIPL1 is present in the developing photoreceptor layer of the human retina and within the photoreceptors of the adult retina reference_section_type: ABSTRACT - id: PMID:14555765 title: AIPL1, a protein implicated in Leber's congenital amaurosis, interacts with and aids in processing of farnesylated proteins. findings: - statement: AIPL1 binds farnesylated proteins and aids their processing. supporting_text: AIPL1 interacts specifically with farnesylated proteins reference_section_type: ABSTRACT - id: PMID:21044950 title: Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells. findings: - statement: The study is a large-scale telomere-interactome screen, not AIPL1-focused mechanistic work. supporting_text: we identified over 300 proteins that associated with the six core telomeric proteins reference_section_type: ABSTRACT - id: PMID:23737531 title: Interaction of aryl hydrocarbon receptor-interacting protein-like 1 with the farnesyl moiety. findings: - statement: AIPL1 binds farnesylated-Cys through its FKBP-like domain. supporting_text: farnesylated-Cys binds exclusively to the FKBP domain of AIPL1 reference_section_type: DISCUSSION - statement: AIPL1 lacks canonical FKBP PPIase activity. supporting_text: the FKBP domain of AIPL1 does not bind FK506 or exhibit peptidylprolylisomerase activity reference_section_type: DISCUSSION - id: PMID:28973376 title: The integrity and organization of the human AIPL1 functional domains is critical for its role as a HSP90-dependent co-chaperone for rod PDE6. findings: - statement: AIPL1 is an HSP90-dependent co-chaperone for rod PDE6. supporting_text: >- AIPL1 functions as a photoreceptor-specific co-chaperone that interacts with the molecular chaperone HSP90 reference_section_type: ABSTRACT - id: PMID:29721967 title: The Leber Congenital Amaurosis-Linked Protein AIPL1 and Its Critical Role in Photoreceptors. findings: - statement: Review summarizing AIPL1 as an HSP90/HSP70 co-chaperone for PDE6. supporting_text: >- AIPL1 functions as a photoreceptor-specific molecular co-chaperone that interacts specifically with the molecular chaperones HSP90 and HSP70 reference_section_type: ABSTRACT - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: - statement: HuRI is a systematic reference map; most individual interactions require contextual follow-up. supporting_text: the cellular function of most individual PPIs remains to be elucidated reference_section_type: DISCUSSION - id: PMID:35065964 title: Molecular insights into the maturation of phosphodiesterase 6 by the specialized chaperone complex of HSP90 with AIPL1. findings: - statement: AIPL1 binds HSP90 and promotes functional maturation of PDE6. supporting_text: AIPL1 preferentially binds to HSP90 in the closed state with a stoichiometry of 1:2 reference_section_type: ABSTRACT - statement: Disrupting AIPL1-HSP90 interaction impairs PDE6 maturation. supporting_text: Disruption of the AIPL1 interaction with HSP90 impedes maturation of PDE6 reference_section_type: RESULTS - id: PMID:32817338 title: The ubiquitin-like modifier FAT10 inhibits retinal PDE6 activity and mediates its proteasomal degradation. full_text_unavailable: true findings: - statement: >- AIPL1 interacts with the ubiquitin-like modifier FAT10 and stabilizes both the FAT10 monomer and the PDE6-FAT10 conjugate; FAT10 conjugates to rod PDE6, targets it for proteasomal degradation, and non-covalently inhibits PDE6 cGMP hydrolysis. FAT10 binds AIPL1 TPR motifs, linking AIPL1 to inflammation-associated PDE6 proteostasis. - id: PMID:38439910 title: Effective AAV-mediated gene replacement therapy in retinal organoids modeling AIPL1-associated LCA4. findings: - statement: >- AAV-mediated AIPL1 gene replacement in human iPSC-derived retinal organoid models of AIPL1-LCA4 rescued the loss of PDE6 and normalized elevated cGMP without changing PDE6 transcript levels, supporting a post-transcriptional proteostasis/assembly mechanism consistent with AIPL1's chaperone role in PDE6 maturation. - id: PMID:41465493 title: 'Restoring Sight: The Journey of AIPL1 from Discovery to Therapy.' findings: - statement: >- Review summarizing AIPL1 as a retina-specific, structurally distinct FKBP-family member essential for PDE6 biogenesis, with FKBP-like, TPR, and primate-specific proline-rich domains, and as the target of LCA4 gene-replacement therapy. - id: file:human/AIPL1/AIPL1-uniprot.txt title: UniProtKB record for human AIPL1 (Q9NZN9) findings: [] - id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv title: Proteostasis PN projected annotations report findings: - statement: >- AIPL1 was projected to heat shock protein binding through the HSP70-HSP90 joint cochaperone class and to PPIase activity through the FKBP-type PPIase branch. supporting_text: AIPL1 reference_section_type: DATABASE_ENTRY