Crystallographic insight into collagen recognition by discoidin domain receptor 2.
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.
Carafoli
Federico
F
Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
Bihan
Dominique
D
Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK.
Stathopoulos
Stavros
S
Division of National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
Konitsiotis
Antonios D
AD
Division of National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
Kvansakul
Marc
M
Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
Farndale
Richard W
RW
Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK.
Leitinger
Birgit
B
Division of National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
Hohenester
Erhard
E
Department of Life Sciences, Imperial College London, London SW7 2AZ, UK. Electronic address: e.hohenester@imperial.ac.uk.
D000595:Amino Acid Sequence; D005075:Biological Evolution; D003094:Collagen / Q000378:metabolism*; D018360:Crystallography, X-Ray; D000070818:Discoidin Domain Receptors; D008958:Models, Molecular; D011485:Protein Binding; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000737:chemistry / Q000378:metabolism*
D011975:Receptors, Mitogen; D003094:Collagen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases