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J. Biol. Chem., Vol. 279, Issue 41, 43330-43335, October 8, 2004

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Crystal Structure of CD26/Dipeptidyl-peptidase IV in Complex with Adenosine Deaminase Reveals a Highly Amphiphilic Interface^*

Wilhelm A. Weihofen, Jiango Liu, Werner Reutter, Wolfram Saenger¶, and Hua Fan||

From the Institut für Chemie/Kristallographie, Freie Universität Berlin, Takustrasse 6, D-14195 Berlin, Germany and the Institut für Molekularbiologie und Biochemie, Charité-Universitätsmedizin Berlin, Arnimallee 22, D-14195 Berlin, Germany

Dipeptidyl-peptidase IV (DPPIV or CD26) is a homodimeric type II membrane glycoprotein in which the two monomers are subdivided into a -propeller domain and an /-hydrolase domain. As dipeptidase, DPPIV modulates the activity of various biologically important peptides and, in addition, DPPIV acts as a receptor for adenosine deaminase (ADA), thereby mediating co-stimulatory signals in T-lymphocytes. The 3.0-Å resolution crystal structure of the complex formed between human DPPIV and bovine ADA presented here shows that each -propeller domain of the DPPIV dimer binds one ADA. At the binding interface, two hydrophobic loops protruding from the -propeller domain of DPPIV interact with two hydrophilic and heavily charged -helices of ADA, giving rise to the highest percentage of charged residues involved in a protein-protein contact reported thus far. Additionally, four glycosides linked to Asn²²⁹ of DPPIV bind to ADA. In the crystal structure of porcine DPPIV, the observed tetramer formation was suggested to mediate epithelial and lymphocyte cell-cell adhesion. ADA binding to DPPIV could regulate this adhesion, as it would abolish tetramerization.

Received for publication, May 5, 2004 , and in revised form, June 3, 2004.

The atomic coordinates and structure factors (code 1W1I) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* These studies have been supported by DFG-Sonderforschungsbereich 449 and Fonds der Chemischen Industrie. 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 a supplemental table.

^¶ To whom correspondence may be addressed. Tel.: 49-30-838-53412; Fax: 49-30-838-56702; E-mail: saenger{at}chemie.fu-berlin.de.

^|| To whom correspondence may be addressed. Tel.: 49-30-8445-1544; Fax: 49-30-8445-1541; E-mail: hua.fan{at}charite.de.

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