Unlocking the MIT gate: STAM activates AMSH autoinhibition
Linda Makhlouf1, Elton Zeqiraj1
1Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
Structure (London, England : 1993)
|August 8, 2025
Summary
STAMBP/AMSH, a deubiquitinase, is autoinhibited by its MIT domain. STAM and ubiquitin chains activate this enzyme, revealing a regulatory mechanism for endosomal trafficking.
Area of Science:
- Biochemistry
- Cell Biology
- Structural Biology
Background:
- Endosomal sorting is crucial for cellular function.
- Deubiquitinases (DUBs) regulate protein function via ubiquitin chains.
- STAMBP/AMSH is a DUB involved in endosomal trafficking.
Purpose of the Study:
- To elucidate the autoinhibitory mechanism of STAMBP/AMSH.
- To understand how STAMBP/AMSH activity is regulated.
- To uncover the structural basis of endosomal sorting regulation.
Main Methods:
- X-ray crystallography
- Biochemical assays
- Structure-function relationship studies
Main Results:
- The microtubule-interacting and transport (MIT) domain of STAMBP/AMSH directly blocks its catalytic site.
- STAM binding and polyubiquitin chains relieve this autoinhibition.
- Structural insights into the dynamic regulation of STAMBP/AMSH.
Conclusions:
- STAMBP/AMSH activity is tightly regulated by autoinhibition and allosteric activation.
- This regulatory mechanism provides a tunable control over deubiquitinase activity.
- Findings advance understanding of endosomal trafficking and DUB regulation.
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