Structure and function of lysosomal phospholipase A2 and lecithin:cholesterol acyltransferase.
Lysosomal phospholipase A2 (LPLA2) and lecithin:cholesterol acyltransferase (LCAT) belong to a structurally uncharacterized family of key lipid-metabolizing enzymes responsible for lung surfactant catabolism and for reverse cholesterol transport, respectively. Whereas LPLA2 is predicted to underlie the development of drug-induced phospholipidosis, somatic mutations in LCAT cause fish eye disease and familial LCAT deficiency. Here we describe several high-resolution crystal structures of human LPLA2 and a low-resolution structure of LCAT that confirms its close structural relationship to LPLA2. Insertions in the α/β hydrolase core of LPLA2 form domains that are responsible for membrane interaction and binding the acyl chains and head groups of phospholipid substrates. The LCAT structure suggests the molecular basis underlying human disease for most of the known LCAT missense mutations, and paves the way for rational development of new therapeutics to treat LCAT deficiency, atherosclerosis and acute coronary syndrome.
1] Life Sciences Institute and the Departments of Pharmacology and Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Alisa
A
Glukhova
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
Vania
V
Hinkovska-Galcheva
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
Robert
R
Kelly
1] Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Department of Ophthalmology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido 060-8543, Japan.
Akira
A
Abe
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
James A
JA
Shayman
Life Sciences Institute and the Departments of Pharmacology and Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
John J G
JJ
Tesmer
D000595:Amino Acid Sequence; D002784:Cholesterol / Q000378:metabolism; D002850:Chromatography, Gel; D018360:Crystallography, X-Ray; D006801:Humans; D008247:Lysosomes / Q000201:enzymology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000737:chemistry* / Q000378:metabolism*; D054467:Phospholipases A2 / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D011663:Pulmonary Surfactants / Q000378:metabolism; D016415:Sequence Alignment
D011663:Pulmonary Surfactants; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D054467:Phospholipases A2