title: Molecular basis for N-terminal acetylation by the heterodimeric NatA complex.
abstract: N-terminal acetylation is ubiquitous among eukaryotic proteins and controls a myriad of biological processes. Of the N-terminal acetyltransferases (NATs) that facilitate this cotranslational modification, the heterodimeric NatA complex has the most diversity for substrate selection and modifies the majority of all N-terminally acetylated proteins. Here, we report the X-ray crystal structure of the 100-kDa holo-NatA complex from Schizosaccharomyces pombe, in the absence and presence of a bisubstrate peptide-CoA-conjugate inhibitor, as well as the structure of the uncomplexed Naa10p catalytic subunit. The NatA-Naa15p auxiliary subunit contains 13 tetratricopeptide motifs and adopts a ring-like topology that wraps around the NatA-Naa10p subunit, an interaction that alters the Naa10p active site for substrate-specific acetylation. These studies have implications for understanding the mechanistic details of other NAT complexes and how regulatory subunits modulate the activity of the broader family of protein acetyltransferases.
authors.affiliation: 1] Program in Gene Expression and Regulation, Wistar Institute, Philadelphia, Pennsylvania, USA. [2] Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Glen
authors.initials: G
authors.lastname: Liszczak
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Goldberg
authors.forename: Håvard
authors.initials: H
authors.lastname: Foyn
authors.forename: E James
authors.initials: EJ
authors.lastname: Petersson
authors.forename: Thomas
authors.initials: T
authors.lastname: Arnesen
authors.forename: Ronen
authors.initials: R
authors.lastname: Marmorstein
mesh_terms: D000123:Acetyltransferases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D020035:Holoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D063209:N-Terminal Acetyltransferase A / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020836:Protein Structure, Quaternary; D021122:Protein Subunits; D012568:Schizosaccharomyces / Q000201:enzymology / Q000235:genetics; D029702:Schizosaccharomyces pombe Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
chemical_list: D020035:Holoenzymes; D021122:Protein Subunits; D029702:Schizosaccharomyces pombe Proteins; D000123:Acetyltransferases; C584468:NatA protein, S pombe; D063209:N-Terminal Acetyltransferase A
references.citation: Biochem J. 2008 Oct 15;415(2):325-31
references.pmid: 18570629
references.citation: J Biol Chem. 2009 Nov 6;284(45):31122-9
references.pmid: 19744929
references.citation: Nature. 1999 May 20;399(6733):221-9
references.pmid: 10353244
references.citation: Bioessays. 1999 Nov;21(11):932-9
references.pmid: 10517866
references.citation: Acta Crystallogr D Biol Crystallogr. 1999 Apr;55(Pt 4):849-61
references.pmid: 10089316
references.citation: J Biol Chem. 1999 Jun 25;274(26):18157-60
references.pmid: 10373413
references.citation: Science. 2010 Feb 19;327(5968):973-7
references.pmid: 20110468
references.citation: Mol Cell Biol. 2010 Apr;30(8):1898-909
references.pmid: 20154145
references.citation: EMBO J. 1992 Jun;11(6):2087-93
references.pmid: 1600941
references.citation: EMBO J. 1999 Nov 1;18(21):6155-68
references.pmid: 10545125
references.citation: Acta Crystallogr D Biol Crystallogr. 2006 Apr;62(Pt 4):439-50
references.pmid: 16552146
references.citation: Acta Crystallogr D Biol Crystallogr. 2005 Apr;61(Pt 4):465-71
references.pmid: 15809496
references.citation: Biochemistry. 2007 Jan 23;46(3):623-9
references.pmid: 17223684
references.citation: PLoS Genet. 2011 Jul;7(7):e1002169
references.pmid: 21750686
references.citation: J Biol Chem. 2003 May 9;278(19):16887-92
references.pmid: 12626510
references.citation: EMBO J. 1989 Jul;8(7):2067-75
references.pmid: 2551674
references.citation: Proc Natl Acad Sci U S A. 2009 May 19;106(20):8157-62
references.pmid: 19420222
references.citation: Science. 2011 Nov 4;334(6056):674-8
references.pmid: 21940857
references.citation: Mol Cell Proteomics. 2011 May;10(5):M110.004580
references.pmid: 21383206
references.citation: Oncol Rep. 2009 Apr;21(4):909-15
references.pmid: 19287988
references.citation: Cancer Res. 2006 Nov 15;66(22):10677-82
references.pmid: 17108104
references.citation: Oncogene. 2006 Jul 20;25(31):4350-60
references.pmid: 16518407
references.citation: Mol Cell Biol. 2009 Jul;29(13):3569-81
references.pmid: 19398576
references.citation: J Biol Chem. 1999 Aug 13;274(33):23027-34
references.pmid: 10438470
references.citation: Methods Enzymol. 1997;276:307-26
references.pmid: 27754618
references.citation: Trends Biochem Sci. 2012 Apr;37(4):152-61
references.pmid: 22405572
references.citation: Cancer Invest. 2009 Dec;27(10):978-83
references.pmid: 19909012
references.citation: BMC Proc. 2009 Aug 04;3 Suppl 6:S3
references.pmid: 19660096
references.citation: Nat Protoc. 2008;3(7):1171-9
references.pmid: 18600222
references.citation: Biochem J. 2005 Mar 15;386(Pt 3):433-43
references.pmid: 15496142
references.citation: Curr Cancer Drug Targets. 2008 Nov;8(7):545-53
references.pmid: 18991565
references.citation: Oncogene. 2013 Jan 17;32(3):269-76
references.pmid: 22391571
references.citation: J Cell Biochem. 2008 Feb 1;103(2):492-508
references.pmid: 17541948
references.citation: Acta Crystallogr D Biol Crystallogr. 2000 Aug;56(Pt 8):965-72
references.pmid: 10944333
references.citation: PLoS One. 2011;6(9):e24713
references.pmid: 21935442
references.citation: J Biol Chem. 2012 Mar 23;287(13):10081-10088
references.pmid: 22311970
references.citation: Methods Mol Biol. 1996;57:31-44
references.pmid: 8849992
references.citation: Cell. 1996 Oct 4;87(1):85-94
references.pmid: 8858151
references.citation: Oncogene. 2002 Aug 1;21(33):5056-68
references.pmid: 12140756
references.citation: Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
references.pmid: 15572765
references.citation: J Biol Chem. 2011 Oct 21;286(42):37002-10
references.pmid: 21900231
references.citation: Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21
references.pmid: 20124702
references.citation: J Mol Biol. 2003 Jan 24;325(4):595-622
references.pmid: 12507466
references.citation: Arch Biochem Biophys. 2005 Jan 1;433(1):212-26
references.pmid: 15581578
references.citation: Cell. 2011 Aug 19;146(4):607-20
references.pmid: 21854985
references.citation: Mol Cell Biol. 2009 Jun;29(11):2913-24
references.pmid: 19332560
references.citation: Biochem Biophys Res Commun. 2003 Aug 15;308(1):1-11
references.pmid: 12890471
references.citation: Cancer Lett. 2008 Jun 8;264(1):83-92
references.pmid: 18325661
references.citation: PLoS Biol. 2011 May;9(5):e1001073
references.pmid: 21655302
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12449-54
references.pmid: 22814378
references.citation: J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
references.pmid: 19461840
references.citation: Mol Cell Biol. 2003 Oct;23(20):7403-14
references.pmid: 14517307
references.citation: J Biol Chem. 2003 Oct 3;278(40):38109-12
references.pmid: 12915400