ZnF-UBP domains regulate deubiquitinase activity by relieving ubiquitin product inhibition
- Author(s)
- Alexandrovics, JA; Agrata, R; Hane, JA; Schenk, P; Cerra, A; Nachbur, U; Gersch, M; Babon, JJ; Komander, D;
- Journal Title
- Nature Communications
- Publication Type
- Jul 17
- Abstract
- 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.
- Publisher
- Springer Nature
- Research Division(s)
- Ubiquitin Signalling; New Medicines and Diagnostics
- PubMed ID
- 42469262
- Publisher's Version
- https://doi.org/10.1038/s41467-026-75469-9
- Open Access at Publisher's Site
https://doi.org/https://doi.org/10.1038/s41467-026-75469-9- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2026-07-23 11:45:23
Last Modified: 2026-07-23 11:46:37