Molecular insights into the maturation of phosphodiesterase 6 by the specialized chaperone complex of HSP90 with AIPL1

Ravi P Yadav; Kimberly Boyd; Nikolai O Artemyev

doi:10.1016/j.jbc.2022.101620

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Molecular insights into the maturation of phosphodiesterase 6 by the specialized chaperone complex of HSP90 with AIPL1

Journal article

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Molecular insights into the maturation of phosphodiesterase 6 by the specialized chaperone complex of HSP90 with AIPL1

Ravi P Yadav, Kimberly Boyd and Nikolai O Artemyev

The Journal of biological chemistry, Vol.298(3), pp.101620-101620

01/20/2022

DOI: 10.1016/j.jbc.2022.101620

PMCID: PMC8857470

PMID: 35065964

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Abstract

Phosphodiesterase 6 (PDE6) is a key effector enzyme in vertebrate phototransduction, and its maturation and function are known to critically depend on a specialized chaperone, aryl hydrocarbon receptor (AhR)-interacting protein-like 1 (AIPL1). Defects in PDE6 and AIPL1 underlie several severe retinal diseases, including retinitis pigmentosa and Leber congenital amaurosis. Here, we characterize the complex of AIPL1 with HSP90 and demonstrate its essential role in promoting the functional conformation of nascent PDE6. Our analysis suggests that AIPL1 preferentially binds to HSP90 in the closed state with a stoichiometry of 1:2, with the tetratricopeptide repeat (TPR) domain and the TPR helix 7 extension of AIPL1 being the main contributors to the AIPL1/HSP90 interface. We demonstrate that mutations of these determinants markedly diminished both the affinity of AIPL1 for HSP90 and the ability of AIPL1 to cochaperone maturation of PDE6 in a heterologous expression system. In addition, the FK506-binding protein (FKBP) domain of AIPL1 encloses a unique prenyl-binding site that anchors AIPL1 to post-translational lipid modifications of PDE6. A mouse model with rod PDE6 lacking farnesylation of its PDE6A subunit revealed normal expression, trafficking, and signaling of the enzyme. Furthermore, AIPL1 was unexpectedly capable of inducing maturation of unprenylated cone PDE6C, while mutant AIPL1 deficient in prenyl binding competently cochaperoned prenylated PDE6C. Thus, we conclude neither sequestration of the prenyl modifications is required for PDE6 maturation to proceed, nor is the FKBP-lipid interaction involved in the conformational switch of the enzyme into the functional state.

Protein Folding

chaperone

HSP90

phosphodiesterase 6

photoreceptor

phototransduction

Details

Title: Subtitle: Molecular insights into the maturation of phosphodiesterase 6 by the specialized chaperone complex of HSP90 with AIPL1
Creators: Ravi P Yadav - Department of Molecular Physiology and Biophysics, The University of Iowa Carver College of Medicine, Iowa City, IA 52242
Kimberly Boyd - Department of Molecular Physiology and Biophysics, The University of Iowa Carver College of Medicine, Iowa City, IA 52242
Nikolai O Artemyev - Department of Molecular Physiology and Biophysics, The University of Iowa Carver College of Medicine, Iowa City, IA 52242
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.298(3), pp.101620-101620
DOI: 10.1016/j.jbc.2022.101620
PMID: 35065964
PMCID: PMC8857470
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: Elsevier Inc
Language: English
Date published: 01/20/2022
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
Record Identifier: 9984211793502771

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