title: Collagen recognition and transmembrane signalling by discoidin domain receptors.
abstract: The discoidin domain receptors, DDR1 and DDR2, are two closely related receptor tyrosine kinases that are activated by triple-helical collagen in a slow and sustained manner. The DDRs have important roles in embryo development and their dysregulation is associated with human diseases, such as fibrosis, arthritis and cancer. The extracellular region of DDRs consists of a collagen-binding discoidin (DS) domain and a DS-like domain. The transmembrane region mediates the ligand-independent dimerisation of DDRs and is connected to the tyrosine kinase domain by an unusually long juxtamembrane domain. The major DDR binding site in fibrillar collagens is a GVMGFO motif (O is hydroxyproline), which is recognised by an amphiphilic trench at the top of the DS domain. How collagen binding leads to DDR activation is not understood. GVMGFO-containing triple-helical peptides activate DDRs with the characteristic slow kinetics, suggesting that the supramolecular structure of collagen is not required. Activation can be blocked allosterically by monoclonal antibodies that bind to the DS-like domain. Thus, collagen most likely causes a conformational change within the DDR dimer, which may lead to the formation of larger DDR clusters. This article is part of a Special Issue entitled: Emerging recognition and activation mechanisms of receptor tyrosine kinases.
authors.affiliation: Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: Federico
authors.initials: F
authors.lastname: Carafoli
authors.forename: Erhard
authors.initials: E
authors.lastname: Hohenester
mesh_terms: D000818:Animals; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D003094:Collagen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000070819:Discoidin Domain Receptor 1; D000070818:Discoidin Domain Receptors; D005786:Gene Expression Regulation; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011975:Receptors, Mitogen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D011975:Receptors, Mitogen; D003094:Collagen; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases
keywords: Collagen; DDR; DS; ECM; JM; RTK; Receptor tyrosine kinase; TM; X-ray crystallography; discoidin; discoidin domain receptor; extracellular matrix; juxtamembrane; mAb; monoclonal antibody; receptor tyrosine kinase; transmembrane