ArticleProceedings of the National Academy of Sciences of the United States of America2017
Unique structural features of the AIPL1-FKBP domain that support prenyl lipid binding and underlie protein malfunction in blindness.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 18 citations in OpenAlex.
- Article
- Redox regulation of PDE6 and cGMP signaling in diabetic retinal neurodegeneration.Biochemistry and biophysics reports · 2026Review
- Restoring Sight: The Journey of AIPL1 from Discovery to Therapy.International journal of molecular sciences · 2025Review
- Updates on protein-prenylation and associated inherited retinopathies.Frontiers in ophthalmology · 2024Review
- Prenylation is essential for the enrichment of cone phosphodiesterase-6 (PDE6) in outer segments and efficient cone phototransduction.Human molecular genetics · 2023Article
- Retinal Organoids from an AIPL1 CRISPR/Cas9 Knockout Cell Line Successfully Recapitulate the Molecular Features of LCA4 Disease.International journal of molecular sciences · 2023Article
- Unique interface and dynamics of the complex of HSP90 with a specialized cochaperone AIPL1.Structure (London, England : 1993) · 2023Article
- The Role of Hsp90 in Retinal Proteostasis and Disease.Biomolecules · 2022Review
- Mutations in Hsp90 Cochaperones Result in a Wide Variety of Human Disorders.Frontiers in molecular biosciences · 2021Review
- Clinical and functional analyses of AIPL1 variants reveal mechanisms of pathogenicity linked to different forms of retinal degeneration.Scientific reports · 2020Article
- Retinal Organoids derived from hiPSCs of an AIPL1-LCA Patient Maintain Cytoarchitecture despite Reduced levels of Mutant AIPL1.Scientific reports · 2020Article
- Interaction of the tetratricopeptide repeat domain of aryl hydrocarbon receptor-interacting protein-like 1 with the regulatory Pγ subunit of phosphodiesterase 6.The Journal of biological chemistry · 2019Article
- FKBP Ligands-Where We Are and Where to Go?Frontiers in pharmacology · 2018Review
- AIPL1: A specialized chaperone for the phototransduction effector.Cellular signalling · 2017Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
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.
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