Structural Basis for the Activation and Inhibition of the UCH37 Deubiquitylase

VanderLinden, Ryan T.; Hemmis, Casey W.; Schmitt, Benjamin; Ndoja, Ada; Whitby, Frank G.; Robinson, Howard; Cohen, Robert E.; Yao, Tingting; Hill, Christopher P.

doi:10.1016/j.molcel.2016.01.014

Cited by 8 publications

(10 citation statements)

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“…12). In support of our findings on BAP1/ASXL1/2, recent crystallography and molecular studies characterized the mechanism of activation of UCH37 by RPN13 (55,56). The most remarkable similarities with BAP1 are the conserved intramolecular interaction between the DEUBAD of RPN13 and the ULD of UCH37 and the stimulatory effect of RPN13 at the level of substrate binding.…”

Section: Discussionsupporting

confidence: 84%

“…Moreover, highly conserved amino acid residues in BAP1 and UCH37 are required for the interaction with the hydrophobic patch of ubiquitin. Finally, similar to ASXM, the DEUBAD of RPN13 also establishes a weak interaction with ubiquitin (55,56). Thus, BAP1 and UCH37 share a highly conserved mechanism of cofactor-mediated DUB activation.…”

Section: Discussionmentioning

confidence: 96%

“…Thus, BAP1 and UCH37 share a highly conserved mechanism of cofactor-mediated DUB activation. Interestingly, INO80 chromatin remodeling factor also possesses a DEUBAD, and through molecular mimicry, this domain associates with and inhibits UCH37 (55,56). Of note, BAP1 also interacts with INO80 ATPase, a component of the INO80 chromatin remodeling complex, and promotes its deubiquitination (29).…”

Section: Discussionmentioning

confidence: 99%

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The BAP1/ASXL2 Histone H2A Deubiquitinase Complex Regulates Cell Proliferation and Is Disrupted in Cancer

Daou

Hammond-Martel

Mashtalir

et al. 2015

Journal of Biological Chemistry

109

121

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Background:The relevance of ASXL2 to the function of the histone H2A deubiquitinase BAP1 remains unknown. Results: ASXL2 promotes the assembly by BAP1 of a composite ubiquitin-binding interface (CUBI) required for DUB activity and coordination of cell proliferation. Conclusion: Cancer-associated mutations of BAP1 disrupt BAP1-ASXL2 interaction and function. Significance: We provide novel insights into BAP1 tumor suppressor function.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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The BAP1/ASXL2 Histone H2A Deubiquitinase Complex Regulates Cell Proliferation and Is Disrupted in Cancer

Daou

Hammond-Martel

Mashtalir

et al. 2015

Journal of Biological Chemistry

109

121

View full text Add to dashboard Cite

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“…Interestingly, UCH37 is also part of another complex, the chromatin-remodelling INO80 complex, in which its activity is inhibited (Yao et al, 2008). Elegant structural studies have revealed that equivalent DEUBiquitylase ADaptor (DEUBAD) domains present in both Rpn13 (also known as ADRM1 in mammals) and INO80G (also known as NFRKB) induce distinct structural rearrangements in UCH37 that result in its activation at the proteasome and inhibition at the INO80 complex, respectively (Sahtoe et al, 2015;VanderLinden et al, 2015).…”

Section: Interacting Partners Of Dubsmentioning

confidence: 99%

Mechanisms of regulation and diversification of deubiquitylating enzyme function

Leznicki

Kulathu

2017

Journal of Cell Science

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Deubiquitylating (or deubiquitinating) enzymes (DUBs) are proteases that reverse protein ubiquitylation and therefore modulate the outcome of this post-translational modification. DUBs regulate a variety of intracellular processes, including protein turnover, signalling pathways and the DNA damage response. They have also been linked to a number of human diseases, such as cancer, and inflammatory and neurodegenerative disorders. Although we are beginning to better appreciate the role of DUBs in basic cell biology and their importance for human health, there are still many unknowns. Central among these is the conundrum of how the small number of ∼100 DUBs encoded in the human genome is capable of regulating the thousands of ubiquitin modification sites detected in human cells. This Commentary addresses the biological mechanisms employed to modulate and expand the functions of DUBs, and sets directions for future research aimed at elucidating the details of these fascinating processes.This article is part of a Minifocus on Ubiquitin Regulation and Function. For further reading, please see related articles: 'Exploitation of the host cell ubiquitin machinery by microbial effector proteins' by Yi-Han Lin and Matthias P. Machner (J. Cell Sci. 130, 1985-1996. 'Cell scientist to watch -Mads Gyrd-Hansen' (J. Cell Sci. 130, 1981-1983.

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“…Apo UCH37 may exhibit some conformational flexibility, but binding of INO80G places the enzyme into an inactive state by both blocking the ubiquitin-binding site and disrupting alignment of the active site. By contrast, binding to RPN13 increases activity above that of unliganded UCH37 by constraining the enzyme's crossover loop and increasing affinity for ubiquitin (98,99).…”

Section: Deubiquitinases Are Surprisingly Flexible Scissorsmentioning

confidence: 99%

Using Protein Motion to Read, Write, and Erase Ubiquitin Signals

Phillips

Corn

2015

Journal of Biological Chemistry

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Eukaryotes use a tiny protein called ubiquitin to send a variety of signals, most often by post-translationally attaching ubiquitins to substrate proteins and to each other, thereby forming polyubiquitin chains. A combination of biophysical, biochemical, and biological studies has shown that complex macromolecular dynamics are central to many aspects of ubiquitin signaling. This review focuses on how equilibrium fluctuations and coordinated motions of ubiquitin itself, the ubiquitin conjugation machinery, and deubiquitinating enzymes enable activity and regulation on many levels, with implications for how such a tiny protein can send so many signals.Ubiquitin was first identified as a small, highly conserved, and heat-stable protein ubiquitously expressed in all eukaryotes and was later shown to be a central regulator of protein homeostasis by directing substrates to the proteasome (1). Since this seminal work in the late 1970s and early 1980s, the covalent modification of substrates with ubiquitin and ubiquitin chains has been shown to control myriad cellular processes (2) and has also been implicated in the pathology and potentially the treatment of numerous diseases (3).Ubiquitin is typically attached to substrate proteins via an isopeptide bond between the flexible C terminus of ubiquitin and the ⑀-amino group of a substrate lysine, although substrate proteins can also be ubiquitinated at their N terminus. The initial modification can be differentiated by conjugation of additional ubiquitin molecules at any of ubiquitin's seven lysine residues or its own N terminus, resulting in the formation of ubiquitin chains. These different chain linkages encode different signals, and tens of thousands of protein isoforms are ubiquitinated in human cells, implying a massive potential regulatory impact for the cell (4). Lys-48 polyubiquitination is the canonical ubiquitin signal marking substrates for degradation by the proteasome (5), although Lys-11 chains have also been shown to encode degradative signals, particularly in the regulation of mitosis (6). Lys-63 and linear chains are involved in driving substrates to specific signaling complexes, including those involved in NF-B signaling (7), whereas Lys-6 chains have been implicated in autophagy (8,9). Although all possible linkages have been detected in cells (10, 11), the functions of Lys-27, Lys-29, and Lys-33 chains are still emerging. The possibility of branched chains and chains of mixed linkages provides further complexity. Because the literature on ubiquitination is vast, we will direct the reader to more exhaustive reviews covering other aspects of ubiquitin signaling throughout this minireview.Ubiquitination of substrates is controlled by the action of three families of enzymes: the ubiquitin activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), and ubiquitin ligases (E3s). Ubiquitin modifications are edited or removed from substrates by deubiquitinating enzymes (DUBs).3 In humans, there are two E1s, 30 -40 E2s, over 600 E3s, and over 100 DUBs, resul...

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Structural Basis for the Activation and Inhibition of the UCH37 Deubiquitylase

Cited by 8 publications

References 0 publications

The BAP1/ASXL2 Histone H2A Deubiquitinase Complex Regulates Cell Proliferation and Is Disrupted in Cancer

The BAP1/ASXL2 Histone H2A Deubiquitinase Complex Regulates Cell Proliferation and Is Disrupted in Cancer

Mechanisms of regulation and diversification of deubiquitylating enzyme function

Using Protein Motion to Read, Write, and Erase Ubiquitin Signals

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