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Crystallographic insight into collagen recognition by discoidin domain receptor 2.

Carafoli F, Bihan D, Stathopoulos S, Konitsiotis AD, Kvansakul M, Farndale RW, Leitinger B, Hohenester E - Structure (2009)

Bottom Line: We have determined the crystal structure of the discoidin domain of human DDR2 bound to a triple-helical collagen peptide.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.

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.

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Sequence Conservation of the Collagen-Binding Site(A) Sequence alignment of the DS domains of human DDR1 and DDR2. The sequence numbering and secondary structure elements of the DDR2 DS domain are indicated above the alignment. Conserved residues and cysteines are highlighted in magenta and green, respectively. Residues that lose ≥5 Å2 of their solvent-accessible surface upon collagen binding are indicated by purple stars.(B) Mapping of conserved residues onto the molecular surface of the DDR2 DS domain. Residues that are identical in DDR1 and DDR2 are in magenta. The Cys73-Cys177 disulfide bridge is in green. Selected conserved residues and nonconserved substitutions in DDR1 are indicated. The collagen peptide is in purple, and the side chains of the GVMGFO motifs of the leading and middle chains are shown as sticks.
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fig5: Sequence Conservation of the Collagen-Binding Site(A) Sequence alignment of the DS domains of human DDR1 and DDR2. The sequence numbering and secondary structure elements of the DDR2 DS domain are indicated above the alignment. Conserved residues and cysteines are highlighted in magenta and green, respectively. Residues that lose ≥5 Å2 of their solvent-accessible surface upon collagen binding are indicated by purple stars.(B) Mapping of conserved residues onto the molecular surface of the DDR2 DS domain. Residues that are identical in DDR1 and DDR2 are in magenta. The Cys73-Cys177 disulfide bridge is in green. Selected conserved residues and nonconserved substitutions in DDR1 are indicated. The collagen peptide is in purple, and the side chains of the GVMGFO motifs of the leading and middle chains are shown as sticks.

Mentions: The central collagen-binding residues of DDR2 delineated by our structure (Trp52, Thr56, Asp69, Arg105, Glu113, and Cys73-Cys177 disulfide bridge) are strictly conserved in DDR1, consistent with the binding of both receptors to fibrillar collagens (Shrivastava et al., 1997; Vogel et al., 1997) and to GVMGFO-containing peptides (authors' unpublished data). Notably, however, several collagen-binding residues outside of the amphiphilic pocket are not conserved: DDR2 residues His110, Ile112, and Asn175 are replaced in DDR1 by Leu110, Lys112, and Ser175, respectively (Figure 5). These substitutions may be responsible for the distinct specificities of the two homologous receptors, such as the exclusive binding of DDR1 to basement membrane collagen IV (Shrivastava et al., 1997; Vogel et al., 1997) and of DDR2 to collagen X (Leitinger and Kwan, 2006).


Crystallographic insight into collagen recognition by discoidin domain receptor 2.

Carafoli F, Bihan D, Stathopoulos S, Konitsiotis AD, Kvansakul M, Farndale RW, Leitinger B, Hohenester E - Structure (2009)

Sequence Conservation of the Collagen-Binding Site(A) Sequence alignment of the DS domains of human DDR1 and DDR2. The sequence numbering and secondary structure elements of the DDR2 DS domain are indicated above the alignment. Conserved residues and cysteines are highlighted in magenta and green, respectively. Residues that lose ≥5 Å2 of their solvent-accessible surface upon collagen binding are indicated by purple stars.(B) Mapping of conserved residues onto the molecular surface of the DDR2 DS domain. Residues that are identical in DDR1 and DDR2 are in magenta. The Cys73-Cys177 disulfide bridge is in green. Selected conserved residues and nonconserved substitutions in DDR1 are indicated. The collagen peptide is in purple, and the side chains of the GVMGFO motifs of the leading and middle chains are shown as sticks.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2807035&req=5

fig5: Sequence Conservation of the Collagen-Binding Site(A) Sequence alignment of the DS domains of human DDR1 and DDR2. The sequence numbering and secondary structure elements of the DDR2 DS domain are indicated above the alignment. Conserved residues and cysteines are highlighted in magenta and green, respectively. Residues that lose ≥5 Å2 of their solvent-accessible surface upon collagen binding are indicated by purple stars.(B) Mapping of conserved residues onto the molecular surface of the DDR2 DS domain. Residues that are identical in DDR1 and DDR2 are in magenta. The Cys73-Cys177 disulfide bridge is in green. Selected conserved residues and nonconserved substitutions in DDR1 are indicated. The collagen peptide is in purple, and the side chains of the GVMGFO motifs of the leading and middle chains are shown as sticks.
Mentions: The central collagen-binding residues of DDR2 delineated by our structure (Trp52, Thr56, Asp69, Arg105, Glu113, and Cys73-Cys177 disulfide bridge) are strictly conserved in DDR1, consistent with the binding of both receptors to fibrillar collagens (Shrivastava et al., 1997; Vogel et al., 1997) and to GVMGFO-containing peptides (authors' unpublished data). Notably, however, several collagen-binding residues outside of the amphiphilic pocket are not conserved: DDR2 residues His110, Ile112, and Asn175 are replaced in DDR1 by Leu110, Lys112, and Ser175, respectively (Figure 5). These substitutions may be responsible for the distinct specificities of the two homologous receptors, such as the exclusive binding of DDR1 to basement membrane collagen IV (Shrivastava et al., 1997; Vogel et al., 1997) and of DDR2 to collagen X (Leitinger and Kwan, 2006).

Bottom Line: We have determined the crystal structure of the discoidin domain of human DDR2 bound to a triple-helical collagen peptide.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.

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.

Show MeSH