The high-resolution crystal structure of human LCAT1
- Resource Type
- Article
- Authors
- Piper, Derek E.; Romanow, William G.; Gunawardane, Ruwanthi N.; Fordstrom, Preston; Masterman, Stephanie; Pan, Oscar; Thibault, Stephen T.; Zhang, Richard; Meininger, David; Schwarz, Margrit; Wang, Zhulun; King, Chadwick; Zhou, Mingyue; Walker, NigelP.C.
- Source
- Journal of Lipid Research; September 2015, Vol. 56 Issue: 9 p1711-1719, 9p
- Subject
- Language
- ISSN
- 00222275; 15397262
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.