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Extended conformation of the proline‐rich domain of human aryl hydrocarbon receptor‐interacting protein‐like 1: implications for retina disease
Author(s) -
Yadav Ravi P,
Majumder Anurima,
Gakhar Lokesh,
Artemyev Nikolai O.
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13223
Subject(s) - tetratricopeptide , mutation , mutant , heteronuclear single quantum coherence spectroscopy , biology , circular dichroism , protein structure , chemistry , biophysics , genetics , biochemistry , stereochemistry , gene , nuclear magnetic resonance spectroscopy
Mutations in the primate‐specific proline‐rich domain ( PRD ) of aryl hydrocarbon receptor‐interacting protein‐like 1 ( AIPL 1) 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 hAIPL 1 and effects of the PRD mutations on protein structure and function. Solution structures of hAIPL 1, hAIPL 1 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 FK 506‐binding and tetratricopeptide domains. The PRD truncation, but not PRD mutations, reduced the molecule's radius of gyration and maximum dimension. We demonstrate that hAIPL 1 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 hAIPL 1 binding to known partners, phosphodiesterase‐6A and HSP 90. We also identified the γ‐subunit of phosphodiesterase‐6 as a novel partner of hAIPL 1 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.Mutations in the proline‐rich domain (PRD) of human AIPL1 cause severe retinal diseases, yet the role of PRD and the mechanisms of PRD mutations are unknown. Here, we describe a SAXS‐derived solution structure of AIPL1 and functional properties of disease‐linked AIPL1‐PRD mutants. This structure and functional analyses provide a framework for understanding the mechanisms of PRD in disease.