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Collagen recognition and transmembrane signalling by discoidin domain receptors

https://doi.org/10.1016/j.bbapap.2012.10.014Get rights and content
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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.

Highlights

► DDR1 and DDR2 are receptor tyrosine kinases that are activated by collagen. ► DDR activation by collagen is slow and sustained. ► The principles of collagen recognition are understood from structural studies. ► The mechanism of transmembrane signalling is currently not understood. ► Possible activation mechanisms are discussed.

Abbreviations

DDR
discoidin domain receptor
DS
discoidin
ECM
extracellular matrix
JM
juxtamembrane
mAb
monoclonal antibody
RTK
receptor tyrosine kinase
TM
transmembrane

Keywords

Receptor tyrosine kinase
Collagen
X-ray crystallography

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This article is part of a Special Issue entitled: Emerging recognition and activation mechanisms of receptor tyrosine kinases.