Structures of lysosomal phospholipase A2, important in cholesterol metabolism
John Tesmer group (University of Michigan) and collaborators
The structure of a membrane-related protein important in
cholesterol metabolism was studied by John Tesmer's group and collaborators
at the University of Michigan, who determined several high-resolution
structures of lysosomal phospholipase A2 (LPLA2) in complex with irreversible
inhibitors and a low-resolution structure of lecithin:cholesterol
acyltransferase (LCAT). These are the first X-ray structures of these key
lipid-metabolizing enzymes. LPLA2 is a lysosomal enzyme involved in the
lung-surfactant metabolism and its inhibition by cationic lipophilic drugs is
predicted to cause drug-induced phospholipidosis. LCAT is important in
reverse cholesterol transport by catalyzing the esterification of cholesterol
in HDL particles, and thus is being investigated for its role in preventing
atherosclerosis. Additionally, missense mutations in the LCAT gene cause two
genetic diseases, fish eye disease and familial LCAT deficiency. Structures
of LPLA2 and LCAT allowed the investigators to understand the mechanisms of
substrate recognition, membrane interaction, and activation by intermolecular
cues such as by HDL. Such knowledge will be useful in developing small
molecule activators and biotherapeutics to treat genetic and cardiovascular
diseases.
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Figure: Reactions and structures of acylated
LPLA2 (left) and LCAT (right) in complex with their preferred acyl-group acceptors,
N-acetyl sphingosine and cholesterol, respectively. |
Citation: Alisa Glukhova, Vania Hinkovska-Galcheva, Robert
Kelly, Akira Abe, James A. Shayman, John J.G. Tesmer , "Structure and
function of lysosomal phospholipase A2 and lecithin:cholesterol
acyltransferase," Nat. Commun. 6, 6250-1 (2015). DOI:
10.1038/ncomms7250
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