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J. Biol. Chem., Vol. 281, Issue 37, 27398-27404, September 15, 2006

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Defining the CD59-C9 Binding Interaction^*

Yuxiang Huang, Fei Qiao, Ruben Abagyan, Starr Hazard^¶, and Stephen Tomlinson¹

From the Departments of Microbiology and Immunology and ^¶Pharmacology, Medical University of South Carolina, South Carolina 29403 and the Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037

CD59 is a membrane glycoprotein that regulates formation of the cytolytic membrane attack complex (MAC or C5b-9) on host cell membranes. It functions by binding to C8 ( chain) and C9 after their structural rearrangement during MAC assembly. Previous studies indicated that the CD59 binding site in C9 was located within a 25-residue disulfide-bonded loop, and in C8 was located within a 51-residue sequence that overlaps the CD59 binding region of C9. By peptide screens and the use of peptides in binding assays, functional assays, and computer modeling and docking studies, we have identified a 6-residue sequence of human C9, spanning residues 365-371, as the primary CD59 recognition domain involved in CD59-mediated regulation of MAC formation. The data also indicate that both C8 and C9 bind to a similar or overlapping site on CD59. Furthermore, data from CD59-peptide docking models are consistent with the C9 binding site on CD59 located at a hydrophobic pocket, putatively identified previously by CD59 mutational and modeling studies.

Received for publication, April 17, 2006 , and in revised form, July 14, 2006.

^* This work was supported by Grant AI 47386 from the National Institutes of Health. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-3.

¹ To whom correspondence should be addressed: Medical University of South Carolina, Dept. of Microbiology and Immunology, 173 Ashley Ave., Charleston, SC 29403. Tel.: 843-792-1450; E-mail: tomlinss{at}musc.edu.

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