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Title: Structural Basis for the Activation and Inhibition of the UCH37 Deubiquitylase

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Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
Report Number(s):
Journal ID: ISSN 1097-2765
DOE Contract Number:
Resource Type:
Journal Article
Resource Relation:
Journal Name: Molecular Cell; Journal Volume: 57; Journal Issue: 5
Country of Publication:
United States

Citation Formats

VanderLinden, R, Hemmis, C, Schmitt, B, Ndoja, A, Whitby, F, Robinson, H, Cohen, R, Yao, T, and Hill, C. Structural Basis for the Activation and Inhibition of the UCH37 Deubiquitylase. United States: N. p., 2015. Web. doi:10.1016/j.molcel.2015.01.016.
VanderLinden, R, Hemmis, C, Schmitt, B, Ndoja, A, Whitby, F, Robinson, H, Cohen, R, Yao, T, & Hill, C. Structural Basis for the Activation and Inhibition of the UCH37 Deubiquitylase. United States. doi:10.1016/j.molcel.2015.01.016.
VanderLinden, R, Hemmis, C, Schmitt, B, Ndoja, A, Whitby, F, Robinson, H, Cohen, R, Yao, T, and Hill, C. 2015. "Structural Basis for the Activation and Inhibition of the UCH37 Deubiquitylase". United States. doi:10.1016/j.molcel.2015.01.016.
title = {Structural Basis for the Activation and Inhibition of the UCH37 Deubiquitylase},
author = {VanderLinden, R and Hemmis, C and Schmitt, B and Ndoja, A and Whitby, F and Robinson, H and Cohen, R and Yao, T and Hill, C},
abstractNote = {},
doi = {10.1016/j.molcel.2015.01.016},
journal = {Molecular Cell},
number = 5,
volume = 57,
place = {United States},
year = 2015,
month = 3
  • Cited by 34
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  • Uch37 is a deubiquitylating enzyme (DUB) that is functionally linked with multiple protein complexes and signal transduction pathways. Uch37 associates with the 26S proteasome through Rpn13 where it serves to remove distal ubiquitin moeities from polyubiquitylated proteins. Uch37's proteasome associated activity was shown to liberate proteins from destruction. However, Uch37 may also specifically facilitate the destruction of inducible nitric oxide synthase and I{kappa}B-{alpha} at the proteasome. Wicks et al. established Uch37's potential to modulate the transforming growth factor-{beta}(TGF-{beta}) signaling cascade, through tis interaction with SMAD7. Yao et al. demonstrated that Uch37 also associates with the Ino80 chromatin-remodeling complex (Ino80 complex),more » which is involved in DNA repair and transcriptional regulation. Uch37's importance in metazoan development was underscored recently as Uch37 knockouts in mice result in prenatal lethality, where mutant embryos had severe defects in brain development. Protein ubiquitylation is an ATP-dependent post-translational modification that serves to signal a wide variety of cellular processes in eukaryotes. A protein cascade, generally comprising three enzymes, functions to activate, transport and specifically transfer ubiquitin to the targeted protein, culminating in an isopeptide linkage between the {epsilon}-amino group of a target protein's lysysl residue and the ubiquitin's terminal carboxylate. Monoubiquitination plays an important role in histone regulation, endocytosis, and viral budding. Further processing of the target protein may be accomplished by ubiquitylation of the protein on a different lysine, or through the formation of polyubiquitin chains, where the best-characterized outcome is destruction of the polyubiquitin-labeled protein in the proteasome. DUBs catalyze the removal of ubiquitin from proteins. This activity serves to reverse the effects of ubiquitination, permit ubiquitin recycling, or liberate free ubiquitin after translation. Uch37, is a cysteine protease from the ubiquitin C-terminal hydrolase (UCH) family. The catalytic domain of UCH enzymes has a central, six-stranded, antiparallel {beta}-sheet that is flanked on each side by {alpha}-helices. Like picornain 3C, UCH family proteins contain a catalytic triad comprising the side chains of cysteine, histidine, and aspartate. in picornain 3C, the aspartate's carboxylate side chain acts to position histidine's imidazole group for general base catalysis, which activates cysteine for nucleophilic attack. UCH enzymes also contain a glutamine, which may serve to stabilize the tetrahedral transition state. The UCH family can be divided into two distinct groups, that is, enzymes solely composed of the globular UCH fold, or enzymes comprising the UCH domain and a C-terminal extension. The latter group can be subdivided based on the composition of the C-terminal extension. Uch37 carries a C-terminal extension. Until now, the structure of a full-length UCH from this structural class has not been reported.« less
  • Lipoxygenase catalysis depends in a critical fashion on the redox properties of a unique mononuclear non-heme iron cofactor. The isolated enzyme contains predominantly, if not exclusively, iron(II), but the catalytically active form of the enzyme has iron(III). The activating oxidation of the iron takes place in a reaction with the hydroperoxide product of the catalyzed reaction. In a second peroxide-dependent process, lipoxygenases are also inactivated. To examine the redox activation/inactivation dichotomy in lipoxygenase chemistry, the interaction between lipoxygenase-1 (and -3) and cumene hydroperoxide was investigated. Cumene hydroperoxide was a reversible inhibitor of the reaction catalyzed by lipoxygenase-1 under standard assaymore » conditions at high substrate concentrations. Reconciliation of the data with the currently held kinetic mechanism requires simultaneous binding of substrate and peroxide. The enzyme also was both oxidized and largely inactivated in a reaction with the peroxide in the absence of substrate. The consequences of this reaction for the enzyme included the hydroxylation at C{beta} of two amino acid side chains in the vicinity of the cofactor, Trp and Leu. The modifications were identified by mass spectrometry and X-ray crystallography. The peroxide-induced oxidation of iron was also accompanied by a subtle rearrangement in the coordination sphere of the non-heme iron atom. Since the enzyme retains catalytic activity, albeit diminished, after treatment with cumene hydroperoxide, the structure of the iron site may reflect the catalytically relevant form of the cofactor.« less
  • Proper activation of protein phosphatase 2A (PP2A) catalytic subunit is central for the complex PP2A regulation and is crucial for broad aspects of cellular function. The crystal structure of PP2A bound to PP2A phosphatase activator (PTPA) and ATPγS reveals that PTPA makes broad contacts with the structural elements surrounding the PP2A active site and the adenine moiety of ATP. PTPA-binding stabilizes the protein fold of apo-PP2A required for activation, and orients ATP phosphoryl groups to bind directly to the PP2A active site. This allows ATP to modulate the metal-binding preferences of the PP2A active site and utilize the PP2A activemore » site for ATP hydrolysis. In vitro, ATP selectively and drastically enhances binding of endogenous catalytic metal ions, which requires ATP hydrolysis and is crucial for acquisition of pSer/Thr-specific phosphatase activity. Furthermore, both PP2A- and ATP-binding are required for PTPA function in cell proliferation and survival. Our results suggest novel mechanisms of PTPA in PP2A activation with structural economy and a unique ATP-binding pocket that could potentially serve as a specific therapeutic target.« less