Journal article
Unique structural features of the AIPL1–FKBP domain that support prenyl lipid binding and underlie protein malfunction in blindness
Proceedings of the National Academy of Sciences - PNAS, Vol.114(32), pp.E6536-E6545
PNAS Plus
08/08/2017
DOI: 10.1073/pnas.1704782114
PMCID: PMC5559027
PMID: 28739921
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.
Details
- Title: Subtitle
- Unique structural features of the AIPL1–FKBP domain that support prenyl lipid binding and underlie protein malfunction in blindness
- Creators
- Ravi P Yadav - Department of Molecular Physiology and BiophysicsLokesh Gakhar - Department of BiochemistryLiping Yu - Department of BiochemistryNikolai O Artemyev - Department of Molecular Physiology and Biophysics
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.114(32), pp.E6536-E6545
- Series
- PNAS Plus
- DOI
- 10.1073/pnas.1704782114
- PMID
- 28739921
- PMCID
- PMC5559027
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Grant note
- EY-10843 / HHS | NIH | National Eye Institute (NEI)
- Alternative title
- Structure-function studies of AIPL1
- Language
- English
- Date published
- 08/08/2017
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Biochemistry and Molecular Biology; Medicine Administration; Ophthalmology and Visual Sciences
- Record Identifier
- 9984025473402771
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