期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 287, 期 28, 页码 23790-23807出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.361550
关键词
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资金
- National Institutes of Health [EY008061, EY009339, DK079221, EY019718]
- National Institutes of Health Grant from NCRR [5P41RR015301-10, P41RR012408]
- National Institutes of Health Grant from NIGMS [8 P41 GM103403-10, P41GM103473]
- United States Department of Energy [DE-AC02-06CH11357]
- Office of Biological and Environmental Research United States Department of Energy
- Office of Basic Energy Sciences of United States Department of Energy
Lecithin: retinol acyltransferase-like proteins, also referred to as HRAS-like tumor suppressors, comprise a vertebrate subfamily of papain-like or NlpC/P60 thiol proteases that function as phospholipid-metabolizing enzymes. HRAS-like tumor suppressor 3, a representative member of this group, plays a key role in regulating triglyceride accumulation and energy expenditure in adipocytes and therefore constitutes a novel pharmacological target for treatment of metabolic disorders causing obesity. Here, we delineate a catalytic mechanism common to lecithin: retinol acyltransferase-like proteins and provide evidence for their alternative robust lipid-dependent acyltransferase enzymatic activity. We also determined high resolution crystal structures of HRAS-like tumor suppressor 2 and 3 to gain insight into their active site architecture. Based on this structural analysis, two conformational states of the catalytic Cys-113 were identified that differ in reactivity and thus could define the catalytic properties of these two proteins. Finally, these structures provide a model for the topology of these enzymes and allow identification of the protein-lipid bilayer interface. This study contributes to the enzymatic and structural understanding of HRAS-like tumor suppressor enzymes.
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