Journal
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS
Volume 1834, Issue 10, Pages 2187-2194Publisher
ELSEVIER
DOI: 10.1016/j.bbapap.2012.10.014
Keywords
Receptor tyrosine kinase; Collagen; X-ray crystallography
Categories
Funding
- Wellcome Trust [083942/Z/07/Z]
- Biotechnology and Biological Sciences Research Council [BB/I011226/1] Funding Source: researchfish
- Wellcome Trust [083942/Z/07/Z] Funding Source: Wellcome Trust
- BBSRC [BB/I011226/1] Funding Source: UKRI
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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. (C) 2012 Elsevier B.V. All rights reserved.
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