title: Structural insights into the assembly and function of the SAGA deubiquitinating module.
abstract: SAGA is a transcriptional coactivator complex that is conserved across eukaryotes and performs multiple functions during transcriptional activation and elongation. One role is deubiquitination of histone H2B, and this activity resides in a distinct subcomplex called the deubiquitinating module (DUBm), which contains the ubiquitin-specific protease Ubp8, bound to Sgf11, Sus1, and Sgf73. The deubiquitinating activity depends on the presence of all four DUBm proteins. We report here the 1.90 angstrom resolution crystal structure of the DUBm bound to ubiquitin aldehyde, as well as the 2.45 angstrom resolution structure of the uncomplexed DUBm. The structure reveals an arrangement of protein domains that gives rise to a highly interconnected complex, which is stabilized by eight structural zinc atoms that are critical for enzymatic activity. The structure suggests a model for how interactions with the other DUBm proteins activate Ubp8 and allows us to speculate about how the DUBm binds to monoubiquitinated histone H2B in nucleosomes.
authors.affiliation: Department of Biophysics and Biophysical Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Nadine L
authors.initials: NL
authors.lastname: Samara
authors.forename: Ajit B
authors.initials: AB
authors.lastname: Datta
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Berndsen
authors.forename: Xiangbin
authors.initials: X
authors.lastname: Zhang
authors.forename: Tingting
authors.initials: T
authors.lastname: Yao
authors.forename: Robert E
authors.initials: RE
authors.lastname: Cohen
authors.forename: Cynthia
authors.initials: C
authors.lastname: Wolberger
mesh_terms: D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D010450:Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000737:chemistry* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism; D009707:Nucleosomes / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000378:metabolism; D015534:Trans-Activators / Q000737:chemistry* / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism*; D057149:Ubiquitinated Proteins / Q000378:metabolism; D054875:Ubiquitination; D014452:Ubiquitins / Q000737:chemistry / Q000378:metabolism; D015032:Zinc / Q000737:chemistry / Q000378:metabolism; D016335:Zinc Fingers
chemical_list: D000447:Aldehydes; D006657:Histones; D009687:Nuclear Proteins; D009707:Nucleosomes; D016601:RNA-Binding Proteins; C507785:SAGA complex, S cerevisiae; C489245:SGF11 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C481300:Sus1 protein, S cerevisiae; D015534:Trans-Activators; D014157:Transcription Factors; D025801:Ubiquitin; D057149:Ubiquitinated Proteins; D014452:Ubiquitins; C051927:ubiquitin-aldehyde; D051548:Histone Acetyltransferases; C515833:Sgf73 protein, S cerevisiae; D010450:Endopeptidases; C503322:UBP8 protein, S cerevisiae; D015032:Zinc
references.citation: Cell. 2002 Dec 27;111(7):1041-54
references.pmid: 12507430
references.citation: Cell. 2006 Mar 24;124(6):1197-208
references.pmid: 16564012
references.citation: Structure. 2006 Aug;14(8):1293-302
references.pmid: 16905103
references.citation: Mutat Res. 2007 May 1;618(1-2):135-48
references.pmid: 17337012
references.citation: Annu Rev Genet. 2009;43:559-99
references.pmid: 19886812
references.citation: Gene Expr Patterns. 2006 Mar;6(3):277-84
references.pmid: 16378762
references.citation: Mol Cell. 2009 Aug 14;35(3):352-64
references.pmid: 19683498
references.citation: J Biol Chem. 2010 Feb 5;285(6):3850-3856
references.pmid: 20007317
references.citation: Nat Cell Biol. 2008 Jun;10(6):707-15
references.pmid: 18488019
references.citation: Genes Dev. 2008 Oct 15;22(20):2811-22
references.pmid: 18923079
references.citation: Genes Dev. 2003 Nov 1;17(21):2648-63
references.pmid: 14563679
references.citation: Protein Sci. 2007 Sep;16(9):2072-5
references.pmid: 17766394
references.citation: Trends Genet. 2006 Oct;22(10):562-70
references.pmid: 16911843
references.citation: Mol Cell Neurosci. 2006 Mar;31(3):438-45
references.pmid: 16325416
references.citation: Mol Biol Cell. 2006 Oct;17(10):4228-36
references.pmid: 16855026
references.citation: Mol Cell Biol. 2005 Feb;25(3):1173-82
references.pmid: 15657442
references.citation: EMBO J. 2001 Sep 17;20(18):5207-18
references.pmid: 11566884
references.citation: EMBO Rep. 2009 Aug;10(8):843-50
references.pmid: 19609321
references.citation: Trends Biochem Sci. 2008 Aug;33(8):369-75
references.pmid: 18603431
references.citation: J Biol Chem. 2006 Dec 8;281(49):38061-70
references.pmid: 17035239
references.citation: Mol Cell. 2009 Mar 27;33(6):727-37
references.pmid: 19328066
references.citation: Mol Biosyst. 2009 Dec;5(12):1797-808
references.pmid: 19734957
references.citation: EMBO J. 2005 Nov 2;24(21):3747-56
references.pmid: 16211010
references.citation: EMBO J. 2008 Jan 23;27(2):394-405
references.pmid: 18188155
references.citation: J Biol Chem. 2007 Feb 2;282(5):3042-9
references.pmid: 17158105
references.citation: Epigenetics Chromatin. 2009 Feb 18;2(1):2
references.pmid: 19226466
references.citation: J Biol Chem. 1986 Aug 5;261(22):10210-7
references.pmid: 3015923
references.citation: Genome Res. 1996 Oct;6(10):965-71
references.pmid: 8908515
references.citation: Curr Opin Cell Biol. 2010 Jun;22(3):374-82
references.pmid: 20363118