Warburg-Cinotti disease variant p.Tyr740Cys enhances catalytic activity of DDR2 kinase
File(s)
Published version
Author(s)
Hao, Ziteng
Leitinger, Birgit
Type
Journal Article
Abstract
The discoidin domain receptor DDR2 is a collagen-binding receptor tyrosine kinase whose dysregulation is associated with a wide range of diseases. Missense mutations in the DDR2 kinase domain cause Warburg-Cinotti syndrome in an autosomal dominant manner. Warburg-Cinotti syndrome is a severe connective tissue disorder, characterised by a range of manifestations including joint contractures of the hand, corneal vascularisation and pannus, skin fusion and infection, keloid plaques and acro-osteolysis. The Warburg-Cinotti variants, p.Leu610Pro and p.Tyr740Cys, were previously hypothesised to cause disease through a gain-of-function mechanism but mechanistic studies addressing this notion have been lacking. Here we show that both disease variants exhibit ligand-independent constitutive autophosphorylation when expressed as full-length proteins in mammalian cells. We also characterised the enzyme kinetics of soluble WT and DDR2-Y740C kinase constructs. WT DDR2 kinase was found to follow the same two-step activation mechanism previously characterised for DDR1 kinase but with enhanced autophosphorylation and substrate phosphorylation rates. Compared with WT DDR2, DDR2-Y740C displayed further enhanced autophosphorylation and substrate phosphorylation rates, but no effect on ATP binding affinity. The increased catalytic rates of unphosphorylated DDR2-Y740C kinase were similar to those of fully phosphorylated WT DDR2, indicating that the missense variant bypasses all autoinhibitory constraints and adopts the fully active kinase conformation. Tyrosine-740 is a residue in the A-loop of DDR2 kinase that forms autoinhibitory hydrogen bonds with key catalytic residues. These hydrogen bonds cannot form in the cysteine-substituted variant, providing a structural explanation for the release of the A-loop from its autoinhibitory conformation.
Editor(s)
Zhou, Jianhong
Date Issued
2025-11-19
Date Acceptance
2025-10-30
Citation
PLoS ONE, 2025, 20 (11)
ISSN
1932-6203
Publisher
Public Library of Science (PLoS)
Journal / Book Title
PLoS ONE
Volume
20
Issue
11
Copyright Statement
© 2025 Hao, Leitinger. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/41259339
PII: PONE-D-25-34746
Subjects
ACTIVATION
AUTOINHIBITION
BINDING
DISCOIDIN DOMAIN RECEPTOR
LOOP TYROSINE PHOSPHORYLATION
MECHANISMS
Multidisciplinary Sciences
MUTATIONS
PROTEIN-KINASES
Science & Technology
Science & Technology - Other Topics
STRUCTURAL BASIS
TRAFFICKING
Publication Status
Published
Coverage Spatial
United States
Article Number
e0336895
Date Publish Online
2025-11-19