The high-resolution crystal structure of human LCAT1

Journal of Lipid Research

William G. Romanow¹  Ruwanthi N. Gunawardane²  Oscar Pan³  Chadwick King³  Margrit Schwarz⁴  David Meininger⁴  Preston Fordstrom⁴  Mingyue Zhou⁴  NigelP.C. Walker⁵  Stephen T. Thibault⁵  Richard Zhang⁵  Stephanie Masterman⁶  Zhulun Wang⁶  Derek E. Piper⁷ 

[1] Therapeutic Discovery Amgen Inc., South San Francisco, CA 94080;To whom correspondence should be addressed;Metabolic Disorders, Amgen Inc., South San Francisco, CA 94080;Therapeutic Discovery Amgen Inc., South San Francisco, CA 94080;Therapeutic Discovery, Amgen Inc., Burnaby, BC V5A1V7, Canada;Therapeutic Discovery, Amgen Inc., Seattle, WA 98119;To whom correspondence should be addressed;

关键词: lecithin:cholesterol acyltransferase;    X-ray crystallography;    high density lipoprotein;    cholesterol;    antibodies;   

DOI  :  

来源: DOAJ

【 摘 要 】

LCAT is intimately involved in HDL maturation and is a key component of the reverse cholesterol transport (RCT) pathway which removes excess cholesterol molecules from the peripheral tissues to the liver for excretion. Patients with loss-of-function LCAT mutations exhibit low levels of HDL cholesterol and corneal opacity. Here we report the 2.65 Å crystal structure of the human LCAT protein. Crystallization required enzymatic removal of N-linked glycans and complex formation with a Fab fragment from a tool antibody. The crystal structure reveals that LCAT has an α/β hydrolase core with two additional subdomains that play important roles in LCAT function. Subdomain 1 contains the region of LCAT shown to be required for interfacial activation, while subdomain 2 contains the lid and amino acids that shape the substrate binding pocket. Mapping the naturally occurring mutations onto the structure provides insight into how they may affect LCAT enzymatic activity.

【 授权许可】

Unknown