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Crystal Structure of LCAT (C31Y) in complex with Fab1
Structural highlights
DiseaseLCAT_HUMAN Fish-eye disease;Familial LCAT deficiency. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionLCAT_HUMAN Central enzyme in the extracellular metabolism of plasma lipoproteins. Synthesized mainly in the liver and secreted into plasma where it converts cholesterol and phosphatidylcholines (lecithins) to cholesteryl esters and lysophosphatidylcholines on the surface of high and low density lipoproteins (HDLs and LDLs). The cholesterol ester is then transported back to the liver. Has a preference for plasma 16:0-18:2 or 18:O-18:2 phosphatidylcholines. Also produced in the brain by primary astrocytes, and esterifies free cholesterol on nascent APOE-containing lipoproteins secreted from glia and influences cerebral spinal fluid (CSF) APOE- and APOA1 levels. Together with APOE and the cholesterol transporter ABCA1, plays a key role in the maturation of glial-derived, nascent lipoproteins. Required for remodeling high-density lipoprotein particles into their spherical forms.[1] Publication Abstract from PubMedLecithin cholesterol acyltransferase (LCAT) is intimately involved in high density lipoprotein (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 A 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 alpha/beta 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. The high resolution crystal structure of human LCAT.,Piper DE, Romanow WG, Gunawardane RN, Fordstrom P, Masterman S, Pan O, Thibault ST, Zhang R, Meininger D, Schwarz M, Wang Z, King C, Zhou M, Walker NP J Lipid Res. 2015 Jul 20. pii: jlr.M059873. PMID:26195816[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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