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April 21st, 2025
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Johns Hopkins University School of Medicine
biophysics
biorxiv

Mechanism of USP21 autoinhibition and histone H2AK119 deubiquitination

Rahman, S.Open in Google Scholar•Morgan, M. T.Open in Google Scholar•Hicks, C. W.Open in Google Scholar•Gwizdala, A.Open in Google Scholar•Wolberger, C.Open in Google Scholar

Monoubiquitinated histone H2A lysine 119 (H2AK119ub) is a signature modification associated with transcriptional silencing and heterochromatin formation. Ubiquitin-specific protease 21 (USP21), one of four major deubiquitinating enzymes (DUBs) that target H2AK119ub, plays critical roles in diverse cellular processes. The molecular mechanisms by which USP21 specifically deubiquitinates H2AK119ub and is regulated is unknown. USP21 contains a C-terminal USP catalytic domain, preceded by an N-terminal intrinsically disordered region (IDR). We determined the cryo-EM structure of the USP21 catalytic domain bound to an H2AK119ub nucleosome, which reveals a recognition mode that differs from that of two other H2AK119-specific DUBs, Polycomb repressive complex and USP16. We unexpectedly discovered that the N-terminal intrinsically disordered region (IDR) of USP21 inhibits the enzyme\'s activity. Using AlphaFold-Multimer to perform a virtual screen of USP21 interactors, we identified kinases that phosphorylate the USP21 IDR and thereby relieve autoinhibition. Modeling of USP21 using AlphaFold3 suggests a structural model explaining the mechnaism of autoinhibition. AlphaFold analysis of other ubiquitin-specific proteases suggests that phosphorylation-regulated autoinhibition may be a feature of multiple USP enzymes. These findings shed liht on the molecular mechanisms of H2AK119 deubiquitination and reveal a novel mode of DUB autoregulation.

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