The Leber Congenital Amaurosis Protein AIPL1 Functions as Part of a Chaperone Heterocomplex

Hidalgo-de-Quintana, Juan; Evans, R. A.; Cheetham, Michael E.; Spuy, Jacqueline van der

doi:10.1167/iovs.07-1576

Cited by 61 publications

(87 citation statements)

References 49 publications

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“…Mutations in AIPL1 cause destabilization of PDE6 and underlie LCA4 (3,8,17,18). In photoreceptor cells, AIPL1 may function as a critical component of a multiprotein chaperone complex involving Hsp90, Hsp70, and other co-chaperones (13). Hsp90/70 proteins interact with the AIPL1 TPR domain, and several LCA-associated mutations within the TPR domain reduced this interaction (13).…”

Section: Discussionmentioning

confidence: 99%

“…In photoreceptor cells, AIPL1 may function as a critical component of a multiprotein chaperone complex involving Hsp90, Hsp70, and other co-chaperones (13). Hsp90/70 proteins interact with the AIPL1 TPR domain, and several LCA-associated mutations within the TPR domain reduced this interaction (13). However, it is not known whether Hsp90/70 proteins directly assist the AIPL1-mediated folding and/or assembly of PDE6.…”

Section: Discussionmentioning

confidence: 99%

“…AIP is a co-chaperone with Hsp90 in the maturation of the aryl hydrocarbon receptor (11), similar to the co-chaperone function of the FKBP and TPR domain-containing immunophilins FKBP51/52 that act on steroid hormone receptors (12). Furthermore, AIPL1 itself was found to interact with Hsp90 and Hsp70 (13). Thus, the function of AIPL1 as an essential component of a retina-specific chaperone complex has been widely hypothesized (3,7,14,15).…”

mentioning

confidence: 84%

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Interaction of Aryl Hydrocarbon Receptor-interacting Protein-like 1 with the Farnesyl Moiety

Majumder

Gopalakrishna

Cheguru

et al. 2013

Journal of Biological Chemistry

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Background: Mutations in AIPL1, a chaperone of the lipidated visual effector phosphodiesterase-6, cause severe childhood blindness. Results: AIPL1 binds the farnesyl lipid moiety. The unique insert region of AIPL1 is critical for this interaction. Conclusion: The AIPL1-farnesyl interaction suggests its role in the interaction with phosphodiesterase-6 and normal function of AIPL1. Significance: This study describes a novel mechanism of AIPL1 in retina disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 84%

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Interaction of Aryl Hydrocarbon Receptor-interacting Protein-like 1 with the Farnesyl Moiety

Majumder

Gopalakrishna

Cheguru

et al. 2013

Journal of Biological Chemistry

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“…32 The CRB1 missense variant p.(G850V) affects a conserved glycine in the second laminin G domain, encoded by one of the most frequently mutated regions in CRB1. Three missense variants in RPE65 affect conserved amino acid residues located in the carotenoid oxygenase that is essential for its isomerohydrolase activity.…”

Section: Pathogenicity Prediction Of Novel Variantsmentioning

confidence: 99%

Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark

et al. 2015

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Leber congenital amaurosis (LCA) represents the most severe form of inherited retinal dystrophies with an onset during the first year of life. Currently, 21 genes are known to be associated with LCA and recurrent mutations have been observed in AIPL1, CEP290, CRB1 and GUCY2D. In addition, sequence analysis of LRAT and RPE65 may be important in view of treatments that are emerging for patients carrying variants in these genes. Screening of the aforementioned variants and genes was performed in 64 Danish LCA probands. Upon the identification of heterozygous variants, Sanger sequencing was performed of the relevant genes to identify the second allele. In combination with prior arrayed primer extension analysis, this led to the identification of two variants in 42 of 86 cases (49%). Remarkably, biallelic RPE65 variants were identified in 16% of the cases, and one novel variant, p.(D110G), was found in seven RPE65 alleles. We also collected all previously published RPE65 variants, identified in 914 alleles of 539 patients with LCA or early-onset retinitis pigmentosa, and deposited them in the RPE65 Leiden Open Variation Database (LOVD). The in silico pathogenicity assessment of the missense and noncanonical splice site variants, as well as an analysis of their frequency in~60 000 control individuals, rendered 864 of the alleles to affect function or probably affect function. This comprehensive database can now be used to select patients eligible for gene augmentation or retinoid supplementation therapies.

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“…Finally, our data reveal that the LCAlinked V71F mutant protein exists predominantly in the closed conformation, which could account for its pathogenicity. These findings lay the ground for future studies of the structure and mechanisms of the full-length AIPL1 and its interplay with other components of the PDE6 chaperone machinery, such as Pγ and HSP90 (22,38).…”

Section: δ111-132mentioning

confidence: 77%

Unique structural features of the AIPL1–FKBP domain that support prenyl lipid binding and underlie protein malfunction in blindness

Yadav

Gakhar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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FKBP-domain proteins (FKBPs) are pivotal modulators of cellular signaling, protein folding, and gene transcription. Aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) is a distinctive member of the FKBP superfamily in terms of its biochemical properties, and it plays an important biological role as a chaperone of phosphodiesterase 6 (PDE6), an effector enzyme of the visual transduction cascade. Malfunction of mutant AIPL1 proteins triggers a severe form of Leber congenital amaurosis and leads to blindness. The mechanism underlying the chaperone activity of AIPL1 is largely unknown, but involves the binding of isoprenyl groups on PDE6 to the FKBP domain of AIPL1. We solved the crystal structures of the AIPL1-FKBP domain and its pathogenic mutant V71F, both in the apo form and in complex with isoprenyl moieties. These structures reveal a module for lipid binding that is unparalleled within the FKBP superfamily. The prenyl binding is enabled by a unique "loop-out" conformation of the β4-α1 loop and a conformational "flip-out" switch of the key W72 residue. A second major conformation of apo AIPL1-FKBP was identified by NMR studies. This conformation, wherein W72 flips into the ligand-binding pocket and renders the protein incapable of prenyl binding, is supported by molecular dynamics simulations and appears to underlie the pathogenicity of the V71F mutant. Our findings offer critical insights into the mechanisms that underlie AIPL1 function in health and disease, and highlight the structural and functional diversity of the FKBPs.F KBP-domain-containing proteins (FKBPs), whose prototypic member is FKBP12, play pivotal roles in cellular signaling, protein folding, and transcription (1-4). In addition to playing these intrinsic cellular roles, FKBPs mediate the effects of the immunosuppressive drugs FK506 and rapamycin (5, 6). Binding of FK506 to FKBP12 creates an interface for calcineurin, whereas binding of rapamycin enables interaction with and inhibition of mammalian target of rapamycin; thus, FKBP12 can initiate two distinct immunosuppressive pathways (7). Many FKBPs are peptidylprolylisomerases (PPIases) that catalyze the cis-trans conversion of peptidylprolyl bonds (8). A wealth of structural information on FKBPs and their complexes with drugs has been gathered over the years. A classic FKBP domain fold is comprised of a half-conical sixstranded β-sheet surrounding a short central α-helix. Both FK506 and rapamycin bind within a prominent and highly conserved hydrophobic cavity between the β-sheet and the α-helix (5). These drugs also contact a hairpin loop of ∼20 aa that links β-strands β5 and β6 and hangs over the cavity (Fig. 1C). Surprisingly, other than the fact that this pocket contributes to the PPIase active site (9), very little is known about its physiological significance or its natural ligands. One of the few examples of such ligands is the type I TGFβ receptor, to which FKBP12 binds via its hydrophobic pocket and hairpin loop (10).Notably, one member of the FKBP family is known to play a ...

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The Leber Congenital Amaurosis Protein AIPL1 Functions as Part of a Chaperone Heterocomplex

Abstract: These findings suggest that AIPL1 may cooperate with both Hsp70 and Hsp90 within a retina-specific chaperone heterocomplex and that the specialized role of AIPL1 in photoreceptors may therefore be facilitated by these molecular chaperones.

Cited by 61 publications

References 49 publications

Interaction of Aryl Hydrocarbon Receptor-interacting Protein-like 1 with the Farnesyl Moiety

Interaction of Aryl Hydrocarbon Receptor-interacting Protein-like 1 with the Farnesyl Moiety

Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark

Unique structural features of the AIPL1–FKBP domain that support prenyl lipid binding and underlie protein malfunction in blindness

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