Structure of Staphylococcus aureus EsxA suggests a contribution to virulence by action as a transport chaperone and/or adaptor protein.
Staphylococcus aureus pathogenesis depends on a specialized protein secretion system (ESX-1) that delivers a range of virulence factors to assist infectivity. We report the characterization of two such factors, EsxA and EsxB, small acidic dimeric proteins carrying a distinctive WXG motif. EsxA crystallized in triclinic and monoclinic forms and high-resolution structures were determined. The asymmetric unit of each crystal form is a dimer. The EsxA subunit forms an elongated cylindrical structure created from side-by-side alpha-helices linked with a hairpin bend formed by the WXG motif. Approximately 25% of the solvent accessible surface area of each subunit is involved in interactions, predominantly hydrophobic, with the partner subunit. Secondary-structure predictions suggest that EsxB displays a similar structure. The WXG motif helps to create a shallow cleft at each end of the dimer, forming a short beta-sheet-like feature with an N-terminal segment of the partner subunit. Structural and sequence comparisons, exploiting biological data on related proteins found in Mycobacterium tuberculosis, suggest that this family of proteins may contribute to pathogenesis by transporting protein cargo through the ESX-1 system exploiting a C-terminal secretion signal and/or are capable of acting as adaptor proteins to facilitate interactions with host receptor proteins.
Sundaramoorthy
Ramasubramanian
R
Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee, UK.
Fyfe
Paul K
PK
Hunter
William N
WN
D000595:Amino Acid Sequence; D000942:Antigens, Bacterial / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D020836:Protein Structure, Quaternary; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D013211:Staphylococcus aureus / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D037521:Virulence Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D018832:Molecular Chaperones; D021122:Protein Subunits; D037521:Virulence Factors
Genome Biol. 2001;2(10):RESEARCH0044
11597336
Methods Enzymol. 1997;276:307-26
27754618
Proc Natl Acad Sci U S A. 2005 Jan 25;102(4):1169-74
15657139
Science. 2006 Sep 15;313(5793):1632-6
16973880
Acta Crystallogr D Biol Crystallogr. 1999 Oct;55(Pt 10):1696-702
10531519
J Mol Biol. 2007 Sep 21;372(3):774-97
17681537
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
15572765
Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W89-93
15980588
Mol Microbiol. 2002 Nov;46(3):709-17
12410828
Nat Struct Biol. 2003 Nov;10(11):948-54
14528295
Infect Immun. 1996 Jan;64(1):16-22
8557334
Nat Struct Biol. 1999 May;6(5):458-63
10331874
Trends Microbiol. 1999 Aug;7(8):315-20
10431204
Acta Crystallogr D Biol Crystallogr. 2005 Apr;61(Pt 4):458-64
15805601
J Infect Dis. 2003 Jan 1;187(1):117-23
12508154
Structure. 2003 Oct;11(10):1207-17
14527389
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2256-68
15572779
Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3
15299374
J Biol Chem. 2005 Oct 7;280(40):33953-9
16048998
Nat Struct Biol. 2003 Oct;10(10):789-93
12958592
Microbiology (Reading). 1999 Dec;145 ( Pt 12):3477-3486
10627045
Acta Crystallogr D Biol Crystallogr. 2006 Jan;62(Pt 1):72-82
16369096
Bioinformatics. 2000 Apr;16(4):404-5
10869041
J Biol Chem. 2004 Sep 10;279(37):38433-40
15234962
Nat Med. 2003 May;9(5):533-9
12692540
J Clin Invest. 2003 May;111(9):1265-73
12727914
Eur J Immunol. 1998 Dec;28(12):3949-58
9862331
Nature. 2004 Jul 29;430(6999):583-6
15195105
Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55
15299926
Infect Immun. 1995 May;63(5):1710-7
7729876
Biochemistry. 2006 Feb 14;45(6):1805-17
16460027
Curr Opin Microbiol. 2007 Oct;10(5):441-6
17950658
Protein Eng. 1992 Dec;5(8):739-48
1287654
Acta Crystallogr D Biol Crystallogr. 2002 Oct;58(Pt 10 Pt 2):1772-9
12351820
J Bacteriol. 2007 Aug;189(16):6028-34
17557817
Acta Crystallogr D Biol Crystallogr. 1999 Mar;55(Pt 3):583-601
10089455
FEBS J. 2006 Apr;273(7):1445-62
16689931
Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):13001-6
14557536
EMBO J. 1999 Mar 15;18(6):1435-46
10075916
Acta Crystallogr D Biol Crystallogr. 2001 Mar;57(Pt 3):401-11
11223517
Trends Microbiol. 2002 May;10(5):209-12
11973144
Microbiol Mol Biol Rev. 2006 Sep;70(3):755-88
16959968
EMBO J. 2005 Jul 20;24(14):2491-8
15973432
Microbiol Mol Biol Rev. 1997 Jun;61(2):136-69
9184008
Clin Infect Dis. 1998 May;26(5):1179-81
9597249
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D247-51
16381856
Infect Immun. 2002 Aug;70(8):4697-700
12117986
Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10037-41
11517324
Nature. 1998 Jun 11;393(6685):537-44
9634230
Microbiol Res. 2009;164(3):253-9
17433643
Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12420-5
14557547
J Biol Chem. 2002 Jun 14;277(24):21598-603
11940590
FASEB J. 1995 Aug;9(11):1013-22
7649401
Microbiology (Reading). 1998 Nov;144 ( Pt 11):3195-3203
9846755
J Mol Biol. 1993 Sep 5;233(1):123-38
8377180
JAMA. 2007 Oct 17;298(15):1803-4
17940239
Cell Microbiol. 2007 Jun;9(6):1376-84
17466013
Nucleic Acids Res. 2004 Mar 19;32(5):1792-7
15034147