Journal
STRUCTURE
Volume 17, Issue 12, Pages 1573-1581Publisher
CELL PRESS
DOI: 10.1016/j.str.2009.10.012
Keywords
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Funding
- Wellcome Trust
- UK Medical Research Council
- BBSRC [BB/D524840/1] Funding Source: UKRI
- MRC [G0500707, G0701121] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/D524840/1] Funding Source: researchfish
- Medical Research Council [G0701121, G0500707] Funding Source: researchfish
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The discoidin domain receptors, DDR1 and DDR2, are widely expressed receptor tyrosine kinases that are activated by triple-helical collagen. They control important aspects of cell behavior and are dysregulated in several human diseases. The major DDR2-binding site in collagens I-III is a GVMGFO motif (O is hydroxyproline) that also binds the matricellular protein SPARC. We have determined the crystal structure of the discoidin domain of human DDR2 bound to a triple-helical collagen peptide. The GVMGFO motifs of two collagen chains are recognized by an amphiphilic pocket delimited by a functionally critical tryptophan residue and a buried salt bridge. Collagen binding results in structural changes of DDR2 surface loops that may be linked to the process of receptor activation. A comparison of the GVMGFO-binding sites of DDR2 and SPARC reveals a striking case of convergent evolution in collagen recognition.
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