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An alternative conformation of human TrpRS suggests a role of zinc in activating non-enzymatic function
- Source :
- RNA Biology
- Publication Year :
- 2017
- Publisher :
- Informa UK Limited, 2017.
-
Abstract
- Tryptophanyl-tRNA synthetase (TrpRS) in vertebrates contains a N-terminal extension in front of the catalytic core. Proteolytic removal of the N-terminal 93 amino acids gives rise to T2-TrpRS, which has potent anti-angiogenic activity mediated through its extracellular interaction with VE-cadherin. Zinc has been shown to have anti-angiogenic effects and can bind to human TrpRS. However, the connection between zinc and the anti-angiogenic function of TrpRS has not been explored. Here we report that zinc binding can induce structural relaxation in human TrpRS to facilitate the proteolytic generation of a T2-TrpRS-like fragment. The zinc-binding site is likely to be contained within T2-TrpRS, and the zinc-bound conformation of T2-TrpRS is mimicked by mutation H130R. We determined the crystal structure of H130R T2-TrpRS at 2.8 Å resolution, which reveals drastically different conformation from that of wild-type (WT) T2-TrpRS. The conformational change creates larger binding surfaces for VE-cadherin as suggested by molecular dynamic simulations. Surface plasmon resonance analysis indicates more than 50-fold increase in binding affinity of H130R T2-TrpRS for VE-cadherin, compared to WT T2-TrpRS. The enhanced interaction is also confirmed by a cell-based binding analysis. These results suggest that zinc plays an important role in activating TrpRS for angiogenesis regulation.
- Subjects :
- Protein Conformation, alpha-Helical
0301 basic medicine
crystal structure
Research Paper - Solicited
Genetic Vectors
Gene Expression
chemistry.chemical_element
Angiogenesis Inhibitors
Tryptophan-tRNA Ligase
Tryptophanyl-tRNA synthetase
Zinc
Molecular Dynamics Simulation
Biology
Crystallography, X-Ray
03 medical and health sciences
Anti-angiogenesis
VE-cadherin
Non enzymatic
Antigens, CD
Escherichia coli
Humans
Protein Interaction Domains and Motifs
Cloning, Molecular
H130R T2-TrpRS
Molecular Biology
chemistry.chemical_classification
DNA ligase
Binding Sites
030102 biochemistry & molecular biology
digestive, oral, and skin physiology
Cell Biology
Cadherins
Recombinant Proteins
Amino acid
Molecular Docking Simulation
030104 developmental biology
chemistry
Biochemistry
Anti angiogenesis
Mutation
Thermodynamics
Protein Conformation, beta-Strand
Function (biology)
Protein Binding
Subjects
Details
- ISSN :
- 15558584 and 15476286
- Volume :
- 15
- Database :
- OpenAIRE
- Journal :
- RNA Biology
- Accession number :
- edsair.doi.dedup.....ee5a36f9ebe1d988b261fa9a02f96932