title: Angiopoietin-like protein 4 inhibition of lipoprotein lipase: evidence for reversible complex formation.
abstract: Elevated triglycerides are associated with an increased risk of cardiovascular disease, and lipoprotein lipase (LPL) is the rate-limiting enzyme for the hydrolysis of triglycerides from circulating lipoproteins. The N-terminal domain of angiopoietin-like protein 4 (ANGPTL4) inhibits LPL activity. ANGPTL4 was previously described as an unfolding molecular chaperone of LPL that catalytically converts active LPL dimers into inactive monomers. Our studies show that ANGPTL4 is more accurately described as a reversible, noncompetitive inhibitor of LPL. We find that inhibited LPL is in a complex with ANGPTL4, and upon dissociation, LPL regains lipase activity. Furthermore, we have generated a variant of ANGPTL4 that is dependent on divalent cations for its ability to inhibit LPL. We show that LPL inactivation by this regulatable variant of ANGPTL4 is fully reversible after treatment with a chelator.
authors: From the Departments of Biochemistry and Biophysics, and.
authors: Michael J
authors: MJ
authors: Lafferty
authors: Kira C
authors: KC
authors: Bradford
authors: Dorothy A
authors: DA
authors: Erie
authors: Saskia B
authors: SB
authors: Neher
mesh_terms: D042682:Angiopoietins / Q000302:isolation & purification / Q000378:metabolism*; D000818:Animals; D055162:Biocatalysis; D002417:Cattle; D002846:Chromatography, Affinity; D003432:Cross-Linking Reagents; D004789:Enzyme Activation; D006493:Heparin; D006358:Hot Temperature; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D018625:Microscopy, Atomic Force; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism*; D012685:Sepharose; D013997:Time Factors
chemical_list: D042682:Angiopoietins; D003432:Cross-Linking Reagents; D046912:Multiprotein Complexes; D006493:Heparin; D012685:Sepharose; D008071:Lipoprotein Lipase
keywords: Angiopoietin-like Protein 4; Atomic Force Microscopy; Enzyme Inhibitors; Enzyme Mechanisms; Lipase; Lipid Metabolism; Lipoprotein Lipase
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