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<p>Most ubiquitin specific protease (USP) deubiquitinases (DUBs) combine non-selective catalytic domains with one or multiple ‘exo’-domains that contribute substrate specificity and localisation, but are generally poorly characterised. Zinc-Finger UBP (ZnF-UBP) domains exist in 12 USP DUBs, yet their function is unclear. We here comprehensively analyse human ZnF-UBP domains, and reveal that 8 of 14 bind ubiquitin (Ub) via an unattached Ub C-terminal GlyGly motif. We focus on USP16, a nucleosome DUB with activity for Ub and Ub-like modifiers, and show that its ZnF-UBP domain can bind substrates, but is also a crucial contributor to enzyme kinetics. Slow Ub release from the catalytic domain after cleavage causes product inhibition, which is overcome in <i>cis</i> by ZnF-UBP-mediated product release. Interestingly, supplying a high affinity product-capturing ZnF-UBP domain in <i>trans</i>, activates USP16 and other USP enzymes. Our data shows the importance of product inhibition as a regulatory mechanism in DUBs, and exemplifies the unappreciated role of exo-domains in regulating DUB function beyond substrate binding.</p>

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ZnF-UBP domains regulate deubiquitinase activity by relieving ubiquitin product inhibition

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月17日

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  • Jack A. Alexandrovics,
  • Rashmi Agrata,
  • Jan André Hane,
  • Philipp Schenk,
  • Anthony Cerra,
  • Ueli Nachbur,
  • Malte Gersch,
  • Jeffrey J. Babon,
  • David Komander

摘要

Most ubiquitin specific protease (USP) deubiquitinases (DUBs) combine non-selective catalytic domains with one or multiple ‘exo’-domains that contribute substrate specificity and localisation, but are generally poorly characterised. Zinc-Finger UBP (ZnF-UBP) domains exist in 12 USP DUBs, yet their function is unclear. We here comprehensively analyse human ZnF-UBP domains, and reveal that 8 of 14 bind ubiquitin (Ub) via an unattached Ub C-terminal GlyGly motif. We focus on USP16, a nucleosome DUB with activity for Ub and Ub-like modifiers, and show that its ZnF-UBP domain can bind substrates, but is also a crucial contributor to enzyme kinetics. Slow Ub release from the catalytic domain after cleavage causes product inhibition, which is overcome in cis by ZnF-UBP-mediated product release. Interestingly, supplying a high affinity product-capturing ZnF-UBP domain in trans, activates USP16 and other USP enzymes. Our data shows the importance of product inhibition as a regulatory mechanism in DUBs, and exemplifies the unappreciated role of exo-domains in regulating DUB function beyond substrate binding.