Abstract
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.
Highlights
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
Genetic mutations of LCAT are responsible for somatic diseases such as familial LCAT deficiency (FLD), resulting from the complete loss of LCAT activity, and fish eye disease (FED)[10], arising from the loss of LCAT activity towards substrates presented on HDL particles
The crystal structure of human LPLA2 (Fig. 1a and Supplementary Fig. 2) was determined to 1.83 Å spacings using protein secreted from HEK293S GnTI À cells and deglycosylated with endoglycosidase F1 (Table 1 and Supplementary Fig. 3a–d)
Summary
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. 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. Are described multiple high-resolution crystal structures of LPLA2 along with a low-resolution structure of LCAT that confirms its close structural homology to LPLA2. These models provide a deeper understanding of the molecular mechanisms underlying substrate selectivity, catalysis and human disease in this important class of lipid-metabolizing enzymes
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