The high-resolution crystal structure of human LCAT.
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.
['Piper|Derek E|DE|', 'Romanow|William G|WG|', 'Gunawardane|Ruwanthi N|RN|', 'Fordstrom|Preston|P|', 'Masterman|Stephanie|S|', 'Pan|Oscar|O|', 'Thibault|Stephen T|ST|', 'Zhang|Richard|R|', 'Meininger|David|D|', 'Schwarz|Margrit|M|', 'Wang|Zhulun|Z|', 'King|Chadwick|C|', 'Zhou|Mingyue|M|', 'Walker|Nigel P C|NP|']
D002784:Cholesterol D018360:Crystallography, X-Ray D006801:Humans D009154:Mutation D007862:Phosphatidylcholine-Sterol O-Acyltransferase D011485:Protein Binding D011487:Protein Conformation D015398:Signal Transduction
cholesterol antibodies X-ray crystallography high density lipoprotein lecithin:cholesterol acyltransferase