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J. Biol. Chem., Vol. 283, Issue 32, 22097-22104, August 8, 2008

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Overexpression of the PDZ1 Domain of PDZK1 Blocks the Activity of Hepatic Scavenger Receptor, Class B, Type I by Altering Its Abundance and Cellular Localization^*

Sara A. Fenske, Ayce Yesilaltay, Rinku Pal, Kathleen Daniels, Attilio Rigotti^¶, Monty Krieger¹, and Olivier Kocher²

From the Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, the Department of Pathology, Beth Israel-Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, and the ^¶Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica, Marcoleta 367, Santiago 833-0024, Chile

PDZK1 is a four-PDZ domain-containing scaffold protein that, via its first PDZ domain (PDZ1), binds to the C terminus of the high density lipoprotein (HDL) receptor scavenger receptor, class B, type I (SR-BI). Abolishing PDZK1 expression in PDZK1 knock-out (KO) mice leads to a post-transcriptional, tissue-specific decrease in SR-BI protein level and an increase in total plasma cholesterol carried in abnormally large HDL particles. Here we show that, although hepatic overexpression of PDZK1 restored normal SR-BI protein abundance and function in PDZK1 KO mice, hepatic overexpression of only the PDZ1 domain was not sufficient to restore normal SR-BI function. In wild-type mice, overexpression of the PDZ1 domain overcame the activity of the endogenous hepatic PDZK1, resulting in a 75% reduction in hepatic SR-BI protein levels and intracellular mislocalization of the remaining SR-BI. As a consequence, the plasma lipoproteins in PDZ1 transgenic mice resembled those in PDZK1 KO mice (hypercholesterolemia due to large HDL). These results indicate that the PDZ1 domain can control the abundance and localization, and therefore the function, of hepatic SR-BI and that structural features of PDZK1 in addition to its SR-BI-binding PDZ1 domain are required for normal hepatic SR-BI regulation.

Received for publication, January 2, 2008 , and in revised form, June 9, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL077780 (to O. K.) and HL64737, HL52212, and HL66105 (to M. K.). This work was also supported by FONDECYT Grant 1070634 (to A. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: Dept. of Biology, Massachusetts Institute of Technology, Rm. 68-483, 77 Massachusetts Ave., Cambridge, MA 02139. Tel.: 617-253-6793; Fax: 617-258-5851; E-mail: krieger{at}mit.edu. ² To whom correspondence may be addressed: Dept. of Pathology, Beth Israel-Deaconess Medical Center and Harvard Medical School, 330 Brookline Ave., Boston, MA 02215. Tel.: 617-667-3598; Fax: 617-667-3591; E-mail: okocher{at}bidmc.harvard.edu.

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