Dynamic networks connect the USP14 active site region with the proteasome interaction surface
Johannes Salomonsson1, Linda Sjöstrand2, Arvid Eskilson1
1Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden.
Protein Science : a Publication of the Protein Society
|March 17, 2025
Summary
Ubiquitin-specific protease 14 (USP14) dynamics were explored using NMR. Small mutations revealed interconnected networks influencing enzyme activity and regulation, offering insights into neurodegeneration and cancer.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Dynamics
Background:
- Ubiquitin-specific protease 14 (USP14) removes ubiquitin, impacting neurodegeneration and cancer.
- Key functional regions of USP14 are known, but its dynamic contributions are unclear.
Purpose of the Study:
- To investigate the dynamic mechanisms underlying USP14 function.
- To explore the allosteric networks connecting USP14's catalytic and regulatory sites.
Main Methods:
- Nuclear Magnetic Resonance (NMR) spectroscopy (structural and dynamical experiments).
- Functional evaluation of site-specific mutations.
- Analysis of protein dynamics on the ps-ms timescale.
Main Results:
- Mutations impacting Ub binding and catalysis induced local and long-range effects.
- A network of dynamic loops connects the catalytic site, Ub binding region, and proteasome interaction surface.
- Varied dynamics were observed in these connecting loops on the ps-ms timescale.
Conclusions:
- USP14 possesses dynamic connections forming allosteric networks.
- These networks link enzyme activity to regulatory functions.
- Findings provide insights into USP14's dynamic regulation and cellular roles.
Keywords:
NMR spectroscopyallosterydeubiquitinases (DUBs)protein dynamicsubiquitin specific proteases (USP)ubiquitin‐proteasome system (UPS)More Related Videos
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