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J. Biol. Chem., Vol. 279, Issue 16, 16629-16637, April 16, 2004

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The Role of a Conserved Acidic Residue in Calcium-dependent Protein Folding for a Low Density Lipoprotein (LDL)-A Module

IMPLICATIONS IN STRUCTURE AND FUNCTION FOR THE LDL RECEPTOR SUPERFAMILY^*

Ying Guo, Xuemei Yu, Kayla Rihani, Qing-Yin Wang, and Lijun Rong¶

From the Department of Microbiology and Immunology, College of Medicine, University of Illinois, Chicago, Illinois 60612

One common feature of the more than 1,000 complement-type repeats (or low density lipoprotein (LDL)-A modules) found in LDL receptor and the other members of the LDL receptor superfamily is a cluster of five highly conserved acidic residues in the C-terminal region, DXXXDXXDXXDE. However, the role of the third conserved aspartate of these LDL-A modules in protein folding and ligand recognition has not been elucidated. In this report, using a model LDL-A module and several experimental approaches, we demonstrate that this acidic residue, like the other four conserved acidic residues, is involved in calcium-dependent protein folding. These results suggest an alternative calcium coordination conformation for the LDL-A modules. The proposed model provides a plausible explanation for the conservation of this acidic residue among the LDL-A modules. Furthermore, the model can explain why mutations of this residue in human LDL receptor cause familial hypercholesterolemia.

Received for publication, January 7, 2004 , and in revised form, January 23, 2004.

^* This work was supported in part by National Institutes of Health Grants CA092459 and AI48056. 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.

Recipient of the American Heart Association Midwest Affiliate pre-doctoral fellowship.

Present address: Harvard Medical School, Boston, MA 02115.

^¶ Recipient of the Schweppe Foundation Career Development award. To whom correspondence should be addressed: Dept. of Microbiology and Immunology, College of Medicine, University of Illinois, E829 MSB, 835 S. Wolcott Ave., Chicago, IL 60612. Tel.: 312-355-0203; Fax: 312-996-6415; E-mail: lijun{at}uic.edu.

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