9NY4

USP21 bound to H2AK119ub nucleosome

Summary for 9NY4

• Entry DOI: 10.2210/pdb9ny4/pdb
• EMDB information: 49919
• Descriptor: Histone H3.2, Histone H4, Histone H2A type 1, ... (8 entities in total)
• Functional Keywords: deubiquitinase, dna-binding protein, dna, nuclear protein
• Biological source: Xenopus laevis (African clawed frog); More
• Total number of polymer chains: 12
• Total formula weight: 249378.73

Authors

Rahman, S.,Wolberger, C. (deposition date: 2025-03-26, release date: 2025-09-24, Last modification date: 2025-10-29)

Primary citation

Rahman, S.,Hicks, C.W.,Gwizdala, A.,Wolberger, C.
Mechanism of USP21 autoinhibition and histone H2AK119 deubiquitination.
Sci Adv, 11:eady2604-eady2604, 2025

PubMed Abstract: Monoubiquitinated histone H2A lysine 119 (H2AK119ub) is a modification associated with transcriptional silencing and heterochromatin formation. Ubiquitin-specific protease 21 (USP21), one of four major H2AK119-specific deubiquitinating enzymes (DUBs), plays critical roles in diverse cellular processes. However, the mechanisms by which USP21 specifically deubiquitinates H2AK119ub and is regulated are unknown. We determined the cryo-EM structure of the USP21 catalytic domain bound to an H2AK119ub nucleosome, which revealed a recognition mode that differs from that of other H2AK119-specific DUBs. We unexpectedly found that the N-terminal 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. AlphaFold3 modeling of USP21 suggests a structural model for autoinhibition. AlphaFold analysis suggests that phosphorylation-regulated autoinhibition may be a feature of various USP enzymes. These findings shed light on the mechanisms of H2AK119 deubiquitination and reveal a previously unexplored mode of phosphorylation-dependent DUB autoregulation.

PubMed: 41071870
DOI: 10.1126/sciadv.ady2604

Experimental method

ELECTRON MICROSCOPY (2.98 Å)