title: Disease mutations in disordered regions--exception to the rule?
abstract: Intrinsically disordered proteins (IDPs) have been implicated in a number of human diseases, including cancer, diabetes, neurodegenerative and cardiovascular disorders. Although for some of these conditions molecular mechanisms are now better understood, the big picture connecting distinct structural properties and functional repertoire of IDPs to pathogenesis and disease progression is still incomplete. Recent studies suggest that signaling and regulatory roles carried out by IDPs require them to be tightly regulated, and that altered IDP abundance may lead to disease. Here, we propose another link between IDPs and disease that takes into account disease-associated missense mutations located in the intrinsically disordered regions. We argue that such mutations are more prevalent and have larger functional impact than previously thought. In addition, we demonstrate that deleterious amino acid substitutions that cause disorder-to-order transitions are particularly enriched among disease mutations compared to neutral polymorphisms. Finally, we discuss potential differences in functional outcomes between disease mutations in ordered and disordered regions, and challenge the conventional structure-centric view of missense mutations.
authors.affiliation: Department of Computer Science, Columbia University, New York, NY 10027, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vacic
authors.forename: Lilia M
authors.initials: LM
authors.lastname: Iakoucheva
mesh_terms: D000818:Animals; D030562:Databases, Protein; D004194:Disease / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics*; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: D011506:Proteins
references.citation: Nucleic Acids Res. 2003 Jul 1;31(13):3812-4
references.pmid: 12824425
references.citation: Cell. 1997 Feb 21;88(4):471-81
references.pmid: 9038338
references.citation: Hum Mutat. 2001 Apr;17(4):263-70
references.pmid: 11295823
references.citation: Mol Syst Biol. 2009;5:321
references.pmid: 19888216
references.citation: J Mol Biol. 2002 Oct 25;323(3):573-84
references.pmid: 12381310
references.citation: Methods Mol Biol. 2010;604:369-93
references.pmid: 20013384
references.citation: Biochemistry. 2010 May 25;49(20):4395-410
references.pmid: 20405910
references.citation: Annu Rev Biophys. 2008;37:215-46
references.pmid: 18573080
references.citation: Trends Genet. 2000 May;16(5):198-200
references.pmid: 10782110
references.citation: Curr Opin Struct Biol. 2011 Jun;21(3):432-40
references.pmid: 21514144
references.citation: PLoS Comput Biol. 2006 Aug 4;2(8):e100
references.pmid: 16884331
references.citation: Trends Genet. 2003 Sep;19(9):505-13
references.pmid: 12957544
references.citation: Mol Biol Evol. 2010 Mar;27(3):609-21
references.pmid: 19923193
references.citation: Nat Rev Mol Cell Biol. 2005 Mar;6(3):197-208
references.pmid: 15738986
references.citation: Proteins. 2010 Feb 1;78(2):365-80
references.pmid: 19722269
references.citation: J Mol Biol. 2002 Sep 27;322(4):891-901
references.pmid: 12270722
references.citation: J Mol Biol. 2004 Mar 26;337(3):635-45
references.pmid: 15019783
references.citation: Pac Symp Biocomput. 2010;:337-47
references.pmid: 19908386
references.citation: Mol Cell. 2008 Feb 29;29(4):525-31
references.pmid: 18313390
references.citation: Genome Biol. 2006;7(6):R45
references.pmid: 16780599
references.citation: Nat Rev Genet. 2004 Aug;5(8):589-97
references.pmid: 15266341
references.citation: Am J Hum Genet. 2007 Nov;81(5):1006-24
references.pmid: 17924342
references.citation: Nat Biotechnol. 2008 Oct;26(10):1135-45
references.pmid: 18846087
references.citation: Hum Mutat. 2010 Mar;31(3):335-46
references.pmid: 20052762
references.citation: J Med Genet. 2000 Dec;37(12):E41
references.pmid: 11106359
references.citation: Nat Genet. 1999 Oct;23(2):185-8
references.pmid: 10508514
references.citation: Science. 2008 Nov 28;322(5906):1365-8
references.pmid: 19039133
references.citation: Curr Opin Struct Biol. 2011 Jun;21(3):441-6
references.pmid: 21482101
references.citation: Proteins. 2001 Jan 1;42(1):38-48
references.pmid: 11093259
references.citation: Bioinformatics. 2005 Aug 15;21(16):3433-4
references.pmid: 15955779
references.citation: Mol Cell Biol. 2007 Feb;27(3):864-77
references.pmid: 17101771
references.citation: Nucleic Acids Res. 2004 Feb 11;32(3):1037-49
references.pmid: 14960716
references.citation: J Mol Biol. 1999 Sep 3;291(5):1055-65
references.pmid: 10518942
references.citation: J Proteome Res. 2007 May;6(5):1882-98
references.pmid: 17391014
references.citation: Curr Opin Struct Biol. 2009 Feb;19(1):31-8
references.pmid: 19157855
references.citation: BMC Bioinformatics. 2006 Mar 22;7:166
references.pmid: 16551372
references.citation: Nucleic Acids Res. 2007 Jan;35(Database issue):D786-93
references.pmid: 17145717
references.citation: J Biol Chem. 2007 May 18;282(20):15057-64
references.pmid: 17371874
references.citation: J Mol Biol. 2002 Jan 25;315(4):771-86
references.pmid: 11812146
references.citation: Hum Mutat. 2008 Mar;29(3):361-6
references.pmid: 18175334
references.citation: Genome Res. 2001 May;11(5):863-74
references.pmid: 11337480
references.citation: Genome Biol. 2011;12(2):R14
references.pmid: 21324131
references.citation: FEBS J. 2005 Oct;272(20):5129-48
references.pmid: 16218947
references.citation: Curr Opin Chem Biol. 2010 Aug;14(4):481-8
references.pmid: 20598937
references.citation: Genome Inform Ser Workshop Genome Inform. 2000;11:161-71
references.pmid: 11700597
references.citation: J Mol Biol. 2001 Mar 23;307(2):683-706
references.pmid: 11254390
references.citation: Trends Biochem Sci. 2008 Jan;33(1):2-8
references.pmid: 18054235
references.citation: Trends Biochem Sci. 2002 Oct;27(10):527-33
references.pmid: 12368089
references.citation: Proteins. 2005;61 Suppl 7:176-182
references.pmid: 16187360
references.citation: Ann Neurol. 2009 Dec;66(6):771-82
references.pmid: 20035514
references.citation: Curr Opin Pharmacol. 2010 Dec;10(6):782-8
references.pmid: 20889377
references.citation: Nat Rev Genet. 2011 Aug 18;12(9):628-40
references.pmid: 21850043
references.citation: Trends Biochem Sci. 2010 Oct;35(10):539-46
references.pmid: 20541943
references.citation: Biochemistry. 2002 May 28;41(21):6573-82
references.pmid: 12022860