title: Structural basis for the activation and inhibition of the UCH37 deubiquitylase.
abstract: The UCH37 deubiquitylase functions in two large and very different complexes, the 26S proteasome and the INO80 chromatin remodeler. We have performed biochemical characterization and determined crystal structures of UCH37 in complexes with RPN13 and NFRKB, which mediate its recruitment to the proteasome and INO80, respectively. RPN13 and NFRKB make similar contacts to the UCH37 C-terminal domain but quite different contacts to the catalytic UCH domain. RPN13 can activate UCH37 by disrupting dimerization, although physiologically relevant activation likely results from stabilization of a surface competent for ubiquitin binding and modulation of the active-site crossover loop. In contrast, NFRKB inhibits UCH37 by blocking the ubiquitin-binding site and by disrupting the enzyme active site. These findings reveal remarkable commonality in mechanisms of recruitment, yet very different mechanisms of regulating enzyme activity, and provide a foundation for understanding the roles of UCH37 in the unrelated proteasome and INO80 complexes.
authors.affiliation: Department of Biochemistry University of Utah School of Medicine, Salt Lake City, UT 84112-5650 USA.
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Vander Linden
authors.affiliation: Department of Biochemistry University of Utah School of Medicine, Salt Lake City, UT 84112-5650 USA.
authors.forename: Casey W
authors.initials: CW
authors.lastname: Hemmis
authors.affiliation: Department of Biochemistry and Molecular Biology Colorado State University, Fort Collins, CO 80523 USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schmitt
authors.affiliation: Department of Biochemistry and Molecular Biology Colorado State University, Fort Collins, CO 80523 USA.
authors.forename: Ada
authors.initials: A
authors.lastname: Ndoja
authors.affiliation: Department of Biochemistry University of Utah School of Medicine, Salt Lake City, UT 84112-5650 USA.
authors.forename: Frank G
authors.initials: FG
authors.lastname: Whitby
authors.affiliation: Biology Department Brookhaven National Laboratory, Upton, NY, 11973 USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Robinson
authors.affiliation: Department of Biochemistry and Molecular Biology Colorado State University, Fort Collins, CO 80523 USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Cohen
authors.affiliation: Department of Biochemistry and Molecular Biology Colorado State University, Fort Collins, CO 80523 USA.
authors.forename: Tingting
authors.initials: T
authors.lastname: Yao
authors.affiliation: Department of Biochemistry University of Utah School of Medicine, Salt Lake City, UT 84112-5650 USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Hill
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: C500781:ADRM1 protein, human; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D046912:Multiprotein Complexes; C072725:NFRKB protein, human; D025801:Ubiquitin; C421245:UCHL5 protein, human; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex