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Identification of Kinase-substrate Pairs Using High Throughput Screening
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Structural Dynamics Analysis of USP14 Activation by AKT-Mediated Phosphorylation
Raju Dash1, Non-Nuoc Tran1, Sung Bae Lee2
1Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Republic of Korea.
Cells
|June 19, 2024
Summary
AKT phosphorylation activates Ubiquitin-specific protease 14 (USP14) by inducing structural changes. This phosphorylation enhances USP14
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Ubiquitin-specific protease 14 (USP14) is a key deubiquitinating enzyme (DUB) associated with the proteasome.
- AKT-mediated phosphorylation at Ser432 is known to activate USP14, influencing global protein degradation via the ubiquitin-proteasome system (UPS).
Purpose of the Study:
- To elucidate the atomic-level molecular mechanism of USP14 activation by AKT phosphorylation.
- To characterize the structural dynamics changes in USP14 upon phosphorylation.
Main Methods:
- Molecular dynamics (MD) simulations were performed on the USP14 catalytic domain in inactive, active, and USP14-ubiquitin complex states.
Main Results:
- Ser432 phosphorylation induced significant conformational changes in USP14's blocking loop (BL), transitioning it from an open loop to a β-sheet structure, crucial for activation.
- Phosphorylation increased the frequency of essential hydrogen bonding and salt bridge interactions between USP14 and ubiquitin, enhancing deubiquitinating activity.
Conclusions:
- Phosphorylation at Ser432 plays a critical role in modulating USP14's local conformational landscape and activity.
- These findings provide insights into USP14-mediated proteasome regulation and potential therapeutic target design.
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