Crystallographic Insight into Collagen Recognition by Discoidin Domain Receptor 2 Academic Article uri icon

abstract

  • 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.

authors

  • Carafoli, Federico
  • Bihan, Dominique
  • Stathopoulos, Stavros
  • Konitsiotis, Antonios D
  • Kvansakul, Marc
  • Farndale, Richard W
  • Leitinger, Birgit
  • Hohenester, Erhard

publication date

  • December 2009