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J. Biol. Chem., Vol. 283, Issue 11, 6861-6868, March 14, 2008

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Characterization of High Affinity Binding Motifs for the Discoidin Domain Receptor DDR2 in Collagen^*

Antonios D. Konitsiotis¹, Nicolas Raynal¹, Dominique Bihan, Erhard Hohenester^¶2, Richard W. Farndale¹³, and Birgit Leitinger¹⁴

From the Division of National Heart and Lung Institute (NHLI), ^¶Division of Cell and Molecular Biology, Imperial College London, London SW7 2AZ and the Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, United Kingdom

The discoidin domain receptors, DDR1 and DDR2, are receptor tyrosine kinases that are activated by native triple-helical collagen. Here we have located three specific DDR2 binding sites by screening the entire triple-helical domain of collagen II, using the Collagen II Toolkit, a set of overlapping triple-helical peptides. The peptide sequence that bound DDR2 with highest affinity interestingly contained the sequence for the high affinity binding site for von Willebrand factor in collagen III. Focusing on this sequence, we used a set of truncated and alanine-substituted peptides to characterize the sequence GVMGFO (O is hydroxyproline) as the minimal collagen sequence required for DDR2 binding. Based on a recent NMR analysis of the DDR2 collagen binding domain, we generated a model of the DDR2-collagen interaction that explains why a triple-helical conformation is required for binding. Triple-helical peptides comprising the DDR2 binding motif not only inhibited DDR2 binding to collagen II but also activated DDR2 transmembrane signaling. Thus, DDR2 activation may be effected by single triple-helices rather than fibrillar collagen.

Received for publication, November 12, 2007 , and in revised form, January 11, 2008.

^* This work was supported by grants from The Wellcome Trust and Medical Research Council. 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 and two supplemental figures.

This article was selected as a Paper of the Week.

¹ These authors contributed equally to this work.

² A Wellcome Trust Senior Fellow.

³ To whom correspondence may be addressed. E-mail: rwf10{at}mole.bio.cam.ac.uk. ⁴ To whom correspondence may be addressed: Molecular Medicine Section, Division of NHLI, Imperial College London, Sir Alexander Fleming Bldg., London SW7 2AZ, United Kingdom. Tel.: 44-20-7594-1591; Fax: 44-20-7594-3100; E-mail: b.leitinger{at}imperial.ac.uk.

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