title: Bioinformatics analysis reveals biophysical and evolutionary insights into the 3-nitrotyrosine post-translational modification in the human proteome.
abstract: Protein 3-nitrotyrosine is a post-translational modification that commonly arises from the nitration of tyrosine residues. This modification has been detected under a wide range of pathological conditions and has been shown to alter protein function. Whether 3-nitrotyrosine is important in normal cellular processes or is likely to affect specific biological pathways remains unclear. Using GPS-YNO2, a recently described 3-nitrotyrosine prediction algorithm, a set of predictions for nitrated residues in the human proteome was generated. In total, 9.27 per cent of the proteome was predicted to be nitratable (27 922/301 091). By matching the predictions against a set of curated and experimentally validated 3-nitrotyrosine sites in human proteins, it was found that GPS-YNO2 is able to predict 73.1 per cent (404/553) of these sites. Furthermore, of these sites, 42 have been shown to be nitrated endogenously, with 85.7 per cent (36/42) of these predicted to be nitrated. This demonstrates the feasibility of using the predicted dataset for a whole proteome analysis. A comprehensive bioinformatics analysis was subsequently performed on predicted and all experimentally validated nitrated tyrosine. This found mild but specific biophysical constraints that affect the susceptibility of tyrosine to nitration, and these may play a role in increasing the likelihood of 3-nitrotyrosine to affect processes, including phosphorylation and DNA binding. Furthermore, examining the evolutionary conservation of predicted 3-nitrotyrosine showed that, relative to non-nitrated tyrosine residues, 3-nitrotyrosine residues are generally less conserved. This suggests that, at least in the majority of cases, 3-nitrotyrosine is likely to have a deleterious effect on protein function and less likely to be important in normal cellular function.
authors: Lowy Cancer Research Centre, Prince of Wales Clinical School,  University of New South Wales, Sydney 2052,  Australia.
authors: John Y
authors: JY
authors: Ng
authors: Lies
authors: L
authors: Boelen
authors: Jason W H
authors: JW
authors: Wong
mesh_terms: D000595:Amino Acid Sequence; D055592:Biophysical Phenomena; D019295:Computational Biology / Q000379:methods; D019143:Evolution, Molecular; D006801:Humans; D013058:Mass Spectrometry; D058977:Molecular Sequence Annotation; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D020543:Proteome / Q000235:genetics* / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D011506:Proteins; D020543:Proteome; C002744:3-nitrotyrosine; D014443:Tyrosine
references: Free Radic Res. 2011 Jan;45(1):59-72
references: 20942567
references: J Immunol. 1999 Mar 15;162(6):3356-66
references: 10092790
references: J Allergy Clin Immunol. 2008 Feb;121(2):355-60
references: 18158173
references: J Pharmacol Exp Ther. 2011 Feb;336(2):313-20
references: 20962031
references: Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14338-43
references: 16176987
references: Mol Biosyst. 2011 Apr;7(4):1197-204
references: 21258675
references: J Cell Mol Med. 2009 Sep;13(9A):2800-21
references: 19602054
references: J Proteome Res. 2007 Jun;6(6):2257-68
references: 17497906
references: Biopolymers. 1983 Dec;22(12):2577-637
references: 6667333
references: Arch Biochem Biophys. 1999 Nov 15;371(2):169-78
references: 10545203
references: Anal Biochem. 2011 Nov 15;418(2):184-96
references: 21855526
references: Nucleic Acids Res. 2011 Jan;39(Database issue):D283-8
references: 20972218
references: Free Radic Res Commun. 1993;18(4):195-9
references: 8396550
references: Curr Protoc Protein Sci. 2012 Aug;Chapter 14:Unit 14.13
references: 22851496
references: J Neurochem. 2009 Nov;111(3):859-69
references: 19737347
references: Adv Cancer Res. 2008;100:35-83
references: 18620092
references: Nat Protoc. 2009;4(1):44-57
references: 19131956
references: Biochem Biophys Res Commun. 2012 Mar 30;420(1):54-60
references: 22402285
references: J Biol Chem. 1998 Jun 5;273(23):14085-9
references: 9603906
references: J Mol Cell Cardiol. 2010 Sep;49(3):354-61
references: 20497906
references: Nat Biotechnol. 2007 Mar;25(3):285-6
references: 17344875
references: Biophys J. 1998 Jul;75(1):422-7
references: 9649402
references: Arch Biochem Biophys. 1992 Nov 1;298(2):446-51
references: 1329657
references: Amino Acids. 2012 Jan;42(1):45-63
references: 20495837
references: Proteomics. 2004 Jun;4(6):1551-61
references: 15174125
references: Bioinformatics. 2006 Jun 15;22(12):1536-7
references: 16632492
references: Methods Mol Biol. 2012;828:255-70
references: 22125150
references: J Proteomics. 2011 Oct 19;74(11):2274-88
references: 21640858
references: J Proteome Res. 2009 Jul;8(7):3222-38
references: 19415921
references: J Surg Res. 2006 Jun 15;133(2):143-9
references: 16360172
references: Free Radic Biol Med. 2006 Feb 1;40(3):453-8
references: 16443160
references: Free Radic Res. 1995 Dec;23(6):537-47
references: 8574348
references: Arch Biochem Biophys. 2000 May 15;377(2):350-6
references: 10845713
references: Neurosci Lett. 1999 Jul 2;269(1):52-4
references: 10821643
references: Am J Physiol Heart Circ Physiol. 2004 Jan;286(1):H22-9
references: 14527943
references: Expert Rev Mol Diagn. 2011 Mar;11(2):207-17
references: 21405971
references: Biochemistry. 2007 Jun 26;46(25):7536-48
references: 17530864
references: Methods Mol Biol. 2009;566:137-63
references: 20058170
references: Mol Cell Proteomics. 2009 Dec;8(12):2642-52
references: 19741252
references: FEBS Lett. 1996 Apr 29;385(1-2):63-6
references: 8641468
references: Cell. 2011 Mar 4;144(5):703-18
references: 21376233
references: Arch Biochem Biophys. 2011 Mar 15;507(2):304-9
references: 21167124
references: Circulation. 2006 Sep 26;114(13):1395-402
references: 16966583
references: Expert Rev Proteomics. 2006 Dec;3(6):611-9
references: 17181475
references: Protein Sci. 2003 Jul;12(7):1406-17
references: 12824487
references: Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3377-82
references: 8622943
references: Methods Enzymol. 1999;301:135-45
references: 9919561
references: J Biol Chem. 2004 Mar 5;279(10):8820-6
references: 14681238
references: BMC Bioinformatics. 2010 Jul 21;11:388
references: 20663120
references: Free Radic Biol Med. 1997;22(6):1055-63
references: 9034245
references: Platelets. 2010;21(6):421-8
references: 20624010
references: Nucleic Acids Res. 1994 Nov 11;22(22):4673-80
references: 7984417
references: Antioxid Redox Signal. 2008 May;10(5):843-89
references: 18220476
references: Anal Biochem. 2002 Jan 15;300(2):252-9
references: 11779118
references: Biochemistry. 1966 Nov;5(11):3582-9
references: 5339594