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Related Experiment Video

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Quantitative Analysis of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Stabilization in a Neural Model of Alzheimer's Disease (AD)

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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.

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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.