J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M700086-JLR200 on March 19, 2007

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Journal of Lipid Research, Vol. 48, 1386-1395, June 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Effects of amino acid substitutions at glycine 420 on SR-BI cholesterol transport function

Saj Parathath1,*, Yolanda F. Darlington1,*, Margarita de la Llera Moya{dagger}, Denise Drazul-Schrader{dagger}, David L. Williams2,*, Michael C. Phillips{dagger}, George H. Rothblat{dagger} and Margery A. Connelly3,§

* Department of Pharmacological Sciences, University Medical Center, Stony Brook University, Stony Brook, NY 11794-8651
{dagger} Division of Gastroenterology and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104-4318
§ Johnson & Johnson Pharmaceutical Research and Development LLC, Spring House, PA 19477-0776

Published, JLR Papers in Press, March 19, 2007.

1 S. Parathath and Y. F. Darlington contributed equally to this work.

2 Deceased.

3 To whom correspondence should be addressed. e-mail: mconnell{at}prdus.jnj.com

Scavenger receptor class B type I (SR-BI) facilitates the uptake of HDL cholesteryl esters (CEs) in a two-step process involving binding of HDL to its extracellular domain and transfer of HDL core CEs to a metabolically active membrane pool, where they are subsequently hydrolyzed by a neutral CE hydrolase. Recently, we characterized a mutant, G420H, which replaced glycine 420 in the extracellular domain of SR-BI with a histidine residue and had a profound effect on SR-BI function. The G420H mutant receptor exhibited a reduced ability to mediate selective HDL CE uptake and was unable to deliver HDL CE for hydrolysis, despite the fact that it retained the ability to bind HDL. This did not hold true if glycine 420 was replaced with an alanine residue; G420A maintained wild-type HDL binding and cholesterol transport activity. To further understand the role that glycine 420 plays in SR-BI function and why there was a disparity between replacing glycine 420 with a histidine versus an alanine, we generated a battery of point mutants by substituting glycine 420 with amino acids possessing side chains that were charged, hydrophobic, polar, or bulky and tested the resulting mutants for their ability to support HDL binding, HDL cholesterol transport, and delivery for hydrolysis. The results indicated that substitution with a negatively charged residue or a proline impaired cell surface expression of SR-BI or its interaction with HDL, respectively. Furthermore, substitution of glycine 420 with a positively charged residue reduced HDL CE uptake as well as its subsequent hydrolysis.

Supplementary key words high density lipoprotein • scavenger receptor class B type I • selective uptake • cholesteryl ester metabolism • free cholesterol • reverse cholesterol transport

Abbreviations: apoA-I, apolipoprotein A-I; BLT-1, blocks lipid transport-1; CE, cholesteryl ester; COE, cholesteryl oleyl ether; FC, free cholesterol; SR-BI, scavenger receptor class B type I


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