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J. Lipid Res.
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Journal of Lipid Research, Vol. 42, 31-40, January 2001
Copyright © 2001 by Lipid Research, Inc.


Original Article

Three arginine residues in apolipoprotein A-I are critical for activation of lecithin:cholesterol acyltransferase

Stein Roosbeeka, Berlinda Vanlooa, Nicolas Duvergerc, Hans Castera, Joke Breynea, Iris De Beuna, Hetal Pateld, Joël Vandekerckhoveb, Carol Shouldersd, Maryvonne Rosseneua, and Frank Peelmana
a Laboratory for Lipoprotein Chemistry, Department of Biochemistry, Ghent University, B-9000 Ghent, Belgium
b Department of Medical Protein Research, Flanders Interuniversity Institute for Biotechnology, B-9000 Ghent, Belgium
c Aventis, Vitry-sur-Seine 94403, France
d MRC Molecular Medicine Group, Clinical Sciences Centre, Hammersmith Hospital, London W12 ONN, UK

Correspondence to: Maryvonne Rosseneu, To whom correspondence should be addressed.

Previous studies have suggested that the helical repeat formed by residues 143;–164 of apolipoprotein A-I (apoA-I) contributes to lecithin:cholesterol acyltransferase (LCAT) activation. To identify specific polar residues involved in this process, we examined residue conservation and topology of apoA-I from all known species. We observed that the hydrophobic/hydrophilic interface of helix 143;–164 contains a cluster of three strictly conserved arginine residues (R149, R153, and R160), and that these residues create the only significant positive electrostatic potential around apoA-I. To test the importance of R149, R153, and R160 in LCAT activation, we generated a series of mutant proteins. These had fluorescence emission, secondary structure, and lipid-binding properties comparable to those of wild-type apoA-I. Mutation of conserved residues R149, R153, and R160 drastically decreased LCAT activity on lipid-protein complexes, whereas control mutations (E146Q, D150N, D157N, R171Q, and A175R) did not decrease LCAT activity by more than 55%. The markedly decreased activities of mutants R149, R153, and R160 resulted from a decrease in the maximal reaction velocity Vmax because the apparent Michaelis-Menten constant Km values were similar for the mutant and wild-type apoA-I proteins.

These data suggest that R149, R153, and R160 participate in apoA-I-mediated activation of LCAT, and support the "belt" model for discoidal rHDL. In this model, residues R149, R153, and R160 do not form salt bridges with the antiparallel apoA-I monomer, but instead are pointing toward the surface of the disc, enabling interactions with LCAT. Roosbeek, S., B. Vanloo, N. Duverger, H. Caster, J. Breyne, I. De Beun, H. Patel, J. Vandekerckhove, C. Shoulders, M. Rosseneu, and F. Peelman. Three arginine residues in apolipoportein A-I are critical for activation of lecithin:cholesterol acyltransferase J. Lipid Res. 2001. 42: 31;–40.

Supplementary key words: HDL, enzyme, lipoprotein, cholesterol


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