Two-step release of kinase autoinhibition in discoidin domain receptor 1
| Autor: | Birgit Leitinger, Douglas Sammon, Erhard Hohenester |
|---|---|
| Přispěvatelé: | Biotechnology and Biological Sciences Research Council (BBSRC), Wellcome Trust |
| Rok vydání: | 2020 |
| Předmět: |
Allosteric regulation
Amino Acid Motifs Receptor tyrosine kinase Gene Expression Regulation Enzymologic Discoidin Domain Receptor 1 Protein Domains Catalytic Domain Humans Kinase activity Phosphorylation Tissue homeostasis X-ray crystallography DDR1 Multidisciplinary biology Chemistry Kinase Autophosphorylation Biological Sciences activation mechanism Cell biology SI Correction biology.protein autoinhibition receptor tyrosine kinase Collagen Discoidin domain |
| Zdroj: | Proc Natl Acad Sci U S A |
| ISSN: | 1091-6490 |
| Popis: | Discoidin domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase with important functions in organogenesis and tissue homeostasis. Aberrant DDR1 activity contributes to the progression of human diseases, including fibrosis and cancer. How DDR1 activity is regulated is poorly understood. We investigated the function of the long intracellular juxtamembrane (JM) region of human DDR1 and found that the kinase-proximal segment, JM4, is an important regulator of kinase activity. Crystal structure analysis revealed that JM4 forms a hairpin that penetrates the kinase active site, reinforcing autoinhibition by the activation loop. Using in vitro enzymology with soluble kinase constructs, we established that release from autoinhibition occurs in two distinct steps: rapid autophosphorylation of the JM4 tyrosines, Tyr569 and Tyr586, followed by slower autophosphorylation of activation loop tyrosines. Mutation of JM4 tyrosines abolished collagen-induced DDR1 activation in cells. The insights may be used to develop allosteric, DDR1-specific, kinase inhibitors. |
| Databáze: | OpenAIRE |
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