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Updated: Aug 19, 2025
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Oligopeptide Competition Assay for Phosphorylation Site Determination
Published on: May 18, 2017
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Dynamics and Allosteric Information Pathways of Unphosphorylated c-Cbl
Tianyi Yang1, Li Han2, Shuanghong Huo1
1Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, 950 Main Street, Worcester, Massachusetts 01610, United States.
Journal of Chemical Information and Modeling
|November 28, 2022
Summary
Human c-Cbl protein dynamics were simulated to understand substrate binding. Substrate binding restricts conformational changes, revealing key residues for allosteric regulation and targeted protein degradation strategies.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Human c-Cbl is a RING-type ligase crucial for protein degradation.
- Understanding c-Cbl conformational dynamics is key to its function.
Purpose of the Study:
- To elucidate conformational changes of c-Cbl upon substrate binding.
- To identify allosteric pathways and critical residues involved in signal transmission.
Main Methods:
- Extensive molecular dynamics simulations (68 μs) of c-Cbl variants.
- Subgraph analysis to visualize allosteric signal transmission pathways.
Main Results:
- Substrate binding restricts c-Cbl's RING domain conformational sampling.
- Phe378 and C-terminal region stabilize the partially open state.
- Identified allosteric hot spots at domain junctions crucial for signal transmission.
Conclusions:
- c-Cbl undergoes significant conformational changes upon substrate binding.
- Allosteric hot spots identified provide targets for drug discovery.
- Subgraph approach is a valuable tool for studying allostery and network visualization.
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