5U9I

Crystal structure of the FKBP domain of human aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) complexed with S-farnesyl-L-cysteine methyl ester

Summary for 5U9I

• Entry DOI: 10.2210/pdb5u9i/pdb
• Related: 5U9A 5U9J 5U9K
• Descriptor: Aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1), FARNESYL (2 entities in total)
• Functional Keywords: aipl1, fkbp, chaperone, pde6, photoreceptor, lca, isoprenyl, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 19533.48

Authors

Yadav, R.P.,Gakhar, L.,Liping, Y.,Artemyev, N.O. (deposition date: 2016-12-16, release date: 2017-07-26, Last modification date: 2023-10-04)

Primary citation

Yadav, R.P.,Gakhar, L.,Yu, L.,Artemyev, N.O.
Unique structural features of the AIPL1-FKBP domain that support prenyl lipid binding and underlie protein malfunction in blindness.
Proc. Natl. Acad. Sci. U.S.A., 114:E6536-E6545, 2017

PubMed 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.

PubMed: 28739921
DOI: 10.1073/pnas.1704782114

Experimental method

X-RAY DIFFRACTION (2.3 Å)