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Review
. 2021 Jan 20;22(3):986.
doi: 10.3390/ijms22030986.

Molecular Mechanisms of DUBs Regulation in Signaling and Disease

Ying Li  1 , David Reverter  1
Affiliations
Review

Molecular Mechanisms of DUBs Regulation in Signaling and Disease

Ying Li et al. Int J Mol Sci. .

Abstract

The large family of deubiquitinating enzymes (DUBs) are involved in the regulation of a plethora of processes carried out inside the cell by protein ubiquitination. Ubiquitination is a basic pathway responsible for the correct protein homeostasis in the cell, which could regulate the fate of proteins through the ubiquitin-proteasome system (UPS). In this review we will focus on recent advances on the molecular mechanisms and specificities found for some types of DUBs enzymes, highlighting illustrative examples in which the regulatory mechanism for DUBs has been understood in depth at the molecular level by structural biology. DUB proteases are responsible for cleavage and regulation of the multiple types of ubiquitin linkages that can be synthesized inside the cell, known as the ubiquitin-code, which are tightly connected to specific substrate functions. We will display some strategies carried out by members of different DUB families to provide specificity on the cleavage of particular ubiquitin linkages. Finally, we will also discuss recent progress made for the development of drug compounds targeting DUB proteases, which are usually correlated to the progress of many pathologies such as cancer and neurodegenerative diseases.

Keywords: DUBs; UPS; USPs; deubiquitinating enzymes; proteasome; protein degradation; structural analysis; ubiquitin; ubiquitin-code.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Active site rearrangements in USP7. (A) Schematic representation of the USP7 domain organization. (B) Model for the activation of USP7 by ubiquitin and ubiquitin-like modifiers (UBL) domains (different colors). (C) Crystal structure of the dimer of the USP7CD-UBL45-ubiquitin complex. Ubiquitin (yellow), the C-terminal peptide after UBL5 (orange). (D) Comparison of the active sites between USP7CD-UBL45-Ub and USP7CD. Active USP catalytic domain (blue), non-active USP catalytic domain (gray). Dotted lines are distances between active site Cys and His residues (PDB: 5JTV, 5FWI).
Figure 2
Figure 2
The structure of Ubp8 in the SAGA deubiquitinating module. (A) Crystal structure of the SAGA DUB module in complex with monoubiquitinated nucleosome (PDB: 4ZUX). (B) View of the complex rotated 180°. (C) Structure of Ubp8/Sgf11/Sus1/Sgf73 bound to ubiquitin aldehyde (PDB: 3MHS). (D) Zoom-up and superposition of the active site with or without the Sgf11-ZnF domain. Ubp8 (blue), Sus1 (orange), Sgf73 (pink), sgf11 (wheat), ubiquitin (yellow), zinc atom (purple) (PDB: 4FJC and 3MHS).
Figure 3
Figure 3
The structure of USP25. (A) Schematic cartoon representation of the USP25 tetramer and dimer assemblies. Each monomer is colored. (B) Crystal structure of the USP25 tetramer (PDB: 5O71 and 6HEL). Each dimer is colored blue or light pink. (C) Crystal structure of the USP25 dimer. IL-loop, coiled-coil insertion and ubiquitin-specific protease (USP)-like domain are marked. (D) Binding interface of the IL-loop with the ubiquitin-binding site of USP25. IL-loop (red), active site (green), binding surface (yellow), the interface contacts of IL-loop are labelled. (E) View of D rotated 90°.
Figure 3
Figure 3
The structure of USP25. (A) Schematic cartoon representation of the USP25 tetramer and dimer assemblies. Each monomer is colored. (B) Crystal structure of the USP25 tetramer (PDB: 5O71 and 6HEL). Each dimer is colored blue or light pink. (C) Crystal structure of the USP25 dimer. IL-loop, coiled-coil insertion and ubiquitin-specific protease (USP)-like domain are marked. (D) Binding interface of the IL-loop with the ubiquitin-binding site of USP25. IL-loop (red), active site (green), binding surface (yellow), the interface contacts of IL-loop are labelled. (E) View of D rotated 90°.
Figure 4
Figure 4
The structure of OTUB1 and E2. (A) Crystal structure of OTUB1. (B) Crystal structure of OTUB1-ubiquitin aldehyde-UBC13~Ub. (C) Superposition of OTUB1 structures in (A,B). Ubiquitin (yellow), UBC13 (green), OTUB1 without ubiquitin (white-blue), OTUB1 with ubiquitin (blue), N-terminal ubiquitin-binding helix (blue) is disordered in the apoenzyme. (PDB: 4DHZ and 2ZFY).
Figure 5
Figure 5
The structure of OTULIN. (A) Structure of OTULIN OTU domain in complex with Met1-di-ubiquitin. OTULIN (blue), ubiquitin (yellow). (B) Rearrangement of the active site residues in the absence (white blue) of bound Met1-di-ubiquitin. (C) Rearrangement of active site residues in the presence (blue) of bound Met1-di-ubiquitin. (D) Superposition of (B,C). (PDB: 3ZNZ and 3ZNV).
Figure 5
Figure 5
The structure of OTULIN. (A) Structure of OTULIN OTU domain in complex with Met1-di-ubiquitin. OTULIN (blue), ubiquitin (yellow). (B) Rearrangement of the active site residues in the absence (white blue) of bound Met1-di-ubiquitin. (C) Rearrangement of active site residues in the presence (blue) of bound Met1-di-ubiquitin. (D) Superposition of (B,C). (PDB: 3ZNZ and 3ZNV).
Figure 6
Figure 6
Structure of Ubiquitin-Bound Rpn11-Rpn8. (A) Structure of Rpn11-Rpn8 with ubiquitin. Ubiquitin (yellow), Rpn11 (blue), Rpn8 (gray), Zinc (purple) (B) Comparison of conserved binding sites of Rpn11 and AMSH-LP for the Ile44-ubiquitin-binding surface. Rpn11 (blue), AMSH-LP (gray). Val83 and Phe87 are from Rpn11, Val328 and Phe332 are from AMSH-LP. (C) Comparison of the active sites of Rpn11 and Rpn11-Ub. (PDB: 5U4P, 5W83, 4O8X and 2ZNV).
Figure 7
Figure 7
Structure of USP12-UAF1-WDR20. (A) Structure of with USP12-UAF1. (B) Structure of with USP12-UAF1(9-580)-Ub. (C) Active site of USP12. (D) Differences of Fingers domain in the absence and presence of UAF1. (E) Structure of USP12-UAF1(9-580)-WDR20. Free USP12 (pink), UAF1(deep blue), WDR20 (green), ubiquitin (yellow). (PDB: 5K16, 518W, 5K1B, and 5K1C).
Figure 7
Figure 7
Structure of USP12-UAF1-WDR20. (A) Structure of with USP12-UAF1. (B) Structure of with USP12-UAF1(9-580)-Ub. (C) Active site of USP12. (D) Differences of Fingers domain in the absence and presence of UAF1. (E) Structure of USP12-UAF1(9-580)-WDR20. Free USP12 (pink), UAF1(deep blue), WDR20 (green), ubiquitin (yellow). (PDB: 5K16, 518W, 5K1B, and 5K1C).
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