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Title: LRAT-specific domain facilitates vitamin A metabolism by domain swapping in HRASLS3

Cellular uptake of vitamin A, production of visual chromophore and triglyceride homeostasis in adipocytes depend on two representatives of the vertebrate N1pC/P60 protein family, lecithin:retinol acyltransferase (LRAT) and HRAS-like tumor suppressor 3 (HRASLS3). Both proteins function as lipid-metabolizing enzymes but differ in their substrate preferences and dominant catalytic activity. The mechanism of this catalytic diversity is not understood. In this paper, by using a gain-of-function approach, we identified a specific sequence responsible for the substrate specificity of N1pC/P60 proteins. A 2.2-Å crystal structure of the HRASLS3-LRAT chimeric enzyme in a thioester catalytic intermediate state revealed a major structural rearrangement accompanied by three-dimensional domain swapping dimerization not observed in native HRASLS proteins. Structural changes affecting the active site environment contributed to slower hydrolysis of the catalytic intermediate, supporting efficient acyl transfer. Finally, these findings reveal structural adaptation that facilitates selective catalysis and mechanism responsible for diverse substrate specificity within the LRAT-like enzyme family.
Authors:
 [1] ;  [1] ;  [1] ;  [1]
  1. Case Western Reserve Univ., Cleveland, OH (United States). School of Medicine. Cleveland Center for Membrane and Structural Biology. Dept. of Pharmacology
Publication Date:
OSTI Identifier:
1168504
Grant/Contract Number:
AC02-06CH11357; EY023948; EY009339; T32 GM007250; P41RR012408; P41GM103473
Type:
Accepted Manuscript
Journal Name:
Nature Chemical Biology
Additional Journal Information:
Journal Volume: 11; Journal Issue: 1; Journal ID: ISSN 1552-4450
Publisher:
Nature Publishing Group
Research Org:
Case Western Reserve Univ., Cleveland, OH (United States)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Inst. of Health (NIH) (United States)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Biochemistry; Enzyme mechanisms; Membranes; X-ray crystallography; acyltransferase; LRAT; vitamin A; retinol; HRAS-like tumor suppressor