Extended conformation of the proline-rich domain of human aryl hydrocarbon receptor-interacting protein-like 1: implications for retina disease

Yadav, Ravi P.; Majumder, Anurima; Gakhar, Lokesh; Artemyev, Nikolai O.

doi:10.1111/jnc.13223

Title: Extended conformation of the proline-rich domain of human aryl hydrocarbon receptor-interacting protein-like 1: implications for retina disease

Journal Article · Wed Jul 01 00:00:00 EDT 2015 · Journal of Neurochemistry

DOI:https://doi.org/10.1111/jnc.13223· OSTI ID:1432850

Yadav, Ravi P. ^[1]; Majumder, Anurima ^[1]; Gakhar, Lokesh ^[1]; Artemyev, Nikolai O. ^[1]

Univ. of Iowa, Iowa City, IA (United States)

Mutations in the primate-specific proline-rich domain (PRD) of aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) are thought to cause Leber congenital amaurosis or dominant cone-rod dystrophy. The role of PRD and the mechanisms of PRD mutations are poorly understood. Here, we have examined properties of hAIPL1 and effects of the PRD mutations on protein structure and function. Solution structures of hAIPL1, hAIPL1_1-316 with PRD truncation, and the P351Δ12 and P376S mutants were examined by small angle X-ray scattering. Our analysis suggests that PRD assumes an extended conformation and does not interact with the FK506-binding and tetratricopeptide domains. The PRD truncation, but not PRD mutations, reduced the molecule's radius of gyration and maximum dimension. We demonstrate that hAIPL1 is a monomeric protein, and its secondary structure and stability are not affected by the PRD mutations. PRD itself is an extended monomeric random coil. The PRD mutations caused little or no changes in hAIPL1 binding to known partners, phosphodiesterase-6A and HSP90. We also identified the γ-subunit of phosphodiesterase-6 as a novel partner of hAIPL1 and hypothesize that this interaction is altered by P351Δ12. Our results highlight the complexity of mechanisms of PRD mutations in disease and the possibility that certain mutations are benign variants.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH)

Grant/Contract Number:: AC02-06CH11357; AC02-05CH11231; EY-10843

OSTI ID:: 1432850

Alternate ID(s):: OSTI ID: 1400716

Journal Information:: Journal of Neurochemistry, Vol. 135, Issue 1; ISSN 0022-3042

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 16 works

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Unique structural features of the AIPL1–FKBP domain that support prenyl lipid binding and underlie protein malfunction in blindness Yadav, Ravi P.; Gakhar, Lokesh; Yu, Liping Proceedings of the National Academy of Sciences, Vol. 114, Issue 32 https://doi.org/10.1073/pnas.1704782114	journal	July 2017
Aryl Hydrocarbon Receptor-interacting Protein-like 1 Is an Obligate Chaperone of Phosphodiesterase 6 and Is Assisted by the γ-Subunit of Its Client Gopalakrishna, Kota N.; Boyd, Kimberly; Yadav, Ravi P. Journal of Biological Chemistry, Vol. 291, Issue 31 https://doi.org/10.1074/jbc.m116.737593	journal	June 2016
Interaction of the tetratricopeptide repeat domain of aryl hydrocarbon receptor–interacting protein–like 1 with the regulatory Pγ subunit of phosphodiesterase 6 Yadav, Ravi P.; Boyd, Kimberly; Yu, Liping Journal of Biological Chemistry, Vol. 294, Issue 43 https://doi.org/10.1074/jbc.ra119.010666	journal	October 2019
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Title: Extended conformation of the proline-rich domain of human aryl hydrocarbon receptor-interacting protein-like 1: implications for retina disease

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