Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 276, Issue 35, Pages 33241-33248Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M100326200
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The reaction of lecithin:cholesterol acyltransferase (LCAT) with high density lipoproteins (RDL) is of critical importance in reverse cholesterol transport, but the structural and functional pathways involved in the regulation of LCAT have not been established. We present evidence for the direct binding of LCAT to alpha (2)-macroglobulin (alpha M-2) in human plasma to form a complex 18.5 nm in diameter. Forty percent of plasma LCAT-HDL was associated with a2M; moreover, most of the LCAT in cerebrospinal fluid and in the medium of cultured human hepatoma cell line was associated with alpha M-2. Purified recombinant human LCAT (rLCAT) labeled with I-125 bound to native and methylamine-activated alpha M-2 (alpha M-2-MA) in vitro in a time- and concentration-dependent manner, and this binding did not depend on the presence of lipid. rLCAT bound to alpha 2M-MA with greater affinity than to alpha 2M. Furthermore, rLCAT did not activate alpha 2M as phosphatidylcholine-specific phospholipase C does. Reconstituted HDL particles (LpA-I) inhibited the binding of rLCAT to alpha M-2 more efficiently than native HDL3 did. LCAT associated with alpha M-2 was enzymatically inactive under both endogenous and exogenous assay conditions. Purified rLCAT alone did not bind to low density lipoprotein receptor-related protein (LRP) as lipoprotein lipase (LPL) does; however, when rLCAT was combined with alpha 2M-MA to form a complex, binding, internalization, and degradation of rLCAT took place in LRPexpressing cells (LRP (+/+)) but not in cells deficient in LRP (LRP (-/-)). It is concluded that the binding of LCAT to alpha 2M inhibits its enzymatic activity. Furthermore, the finding supports the possibility that the LRP receptor can act in vivo to mediate clearance of the LCAT-alpha M-2 complex and may significantly influence the bioavailability of LCAT.
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