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  • br Acknowledgements br Introduction Supramolecular collagen

    2019-08-16


    Acknowledgements
    Introduction Supramolecular collagen assemblies are crucial for the mechanical stability of animal bodies (Myllyharju and Kivirikko, 2004). The basic collagen structure is a triple helix of three chains containing multiple Gly-X-X\' repeats; X and X\' are often proline and 4-hydroxyproline (Hyp, O), respectively (Brodsky and Persikov, 2005). Apart from their prominent structural roles, collagens have fundamental functions in cell adhesion and signaling, by serving as ligands for a diverse set of cellular receptors (Heino, 2007, Leitinger and Hohenester, 2007). The most widely distributed collagen receptors are a subclass of β1 integrins and two homologous receptor tyrosine kinases (RTKs), the discoidin domain receptors, DDR1 and DDR2. While collagen binding and signaling by integrins are understood in atomic detail (Emsley et al., 2000, Hynes, 2002), much less is known about the DDRs. Binding of triple-helical collagen to DDRs results in slow and sustained receptor phosphorylation (Shrivastava et al., 1997, Vogel et al., 1997), ultimately regulating many aspects of cell proliferation, adhesion, and migration, as well as remodeling of the extracellular matrix (Vogel et al., 2006). Mice lacking DDR1 exhibit defective mammary gland development (Vogel et al., 2001), kidney function (Gross et al., 2004), and arterial wound repair (Hou et al., 2001). Mice lacking DDR2 exhibit dwarfism resulting from reduced chondrocyte proliferation (Kano et al., 2008, Labrador et al., 2001); a similar 4EGI-1 is observed in human patients with mutations in the DDR2 gene (Bargal et al., 2009). Aberrant DDR function in humans is also associated with osteoarthritis, fibrosis, and cancer (Vogel et al., 2006). Structurally, the DDRs are characterized by an extracellular region consisting of a discoidin (DS) domain that is followed by a domain unique to DDRs, a transmembrane helix, a large cytoplamic juxtamembrane region, and, finally, a C-terminal kinase domain. Several loops within the DS domain have been shown to be essential for collagen binding (Abdulhussein et al., 2004, Ichikawa et al., 2007, Leitinger, 2003), but how collagen is recognized has remained unknown. We recently identified a GVMGFO motif as the major DDR2-binding site in collagens I–III (Konitsiotis et al., 2008). Here, we report the crystal structure of the DS domain of human DDR2 bound to a triple-helical collagen peptide containing this motif. The structure reveals that the apolar GVMGFO motifs of two collagen chains are recognized by an amphiphilic pocket in DDR2, in a manner that is fundamentally different from the metal ion-dependent mechanism employed by integrins.
    Results
    Discussion Cell-collagen interactions are critical for tissue stability and function, but structural studies are difficult because of the large size and structural complexity of collagens. Comprehensive sets of synthetic triple-helical peptides (“Collagen Toolkits”) have been invaluable in defining specific receptor-binding sites in collagens (Farndale et al., 2008) and have made possible crystallographic studies of receptor-collagen complexes. However, to date, α2 integrin has been the only collagen receptor for which the mode of collagen binding was understood in atomic detail (Emsley et al., 2000). We have determined a high-resolution crystal structure of the DDR2 DS domain in complex with a 28-residue collagen peptide, revealing how DDR2 recognizes a conserved GVMGFO motif present in the fibrillar collagens I–III (note that in our peptide methionine is replaced by norleucine; see above). The two large apolar residues of this motif, M and F, are inserted into a specificity pocket at the top of the DDR2 DS domain. This pocket is surprisingly polar on one side, allowing multiple hydrogen-bonding interactions with the O of the GVMGFO motif. An important feature of the DDR2-collagen interaction, correctly predicted from modeling (Konitsiotis et al., 2008), is that the key collagen residues are not provided by the same chain, explaining why a triple-helical conformation is required for binding (Leitinger, 2003, Vogel et al., 1997).