Structured States of Disordered Proteins from Genomic Sequences.
Protein flexibility ranges from simple hinge movements to functional disorder. Around half of all human proteins contain apparently disordered regions with little 3D or functional information, and many of these proteins are associated with disease. Building on the evolutionary couplings approach previously successful in predicting 3D states of ordered proteins and RNA, we developed a method to predict the potential for ordered states for all apparently disordered proteins with sufficiently rich evolutionary information. The approach is highly accurate (79%) for residue interactions as tested in more than 60 known disordered regions captured in a bound or specific condition. Assessing the potential for structure of more than 1,000 apparently disordered regions of human proteins reveals a continuum of structural order with at least 50% with clear propensity for three- or two-dimensional states. Co-evolutionary constraints reveal hitherto unseen structures of functional importance in apparently disordered proteins.
Department of Systems Biology, Harvard Medical School, Harvard University, Boston, MA 02115, USA.
Agnes
A
Toth-Petroczy
Department of Systems Biology, Harvard Medical School, Harvard University, Boston, MA 02115, USA; Division of Medical Sciences, Harvard University, Cambridge, MA 02138, USA; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Perry
P
Palmedo
Department of Systems Biology, Harvard Medical School, Harvard University, Boston, MA 02115, USA.
John
J
Ingraham
Department of Systems Biology, Harvard Medical School, Harvard University, Boston, MA 02115, USA.
Thomas A
TA
Hopf
Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Bonnie
B
Berger
Department of Cell Biology, Harvard Medical School, Harvard University, Boston, MA 02115, USA.
Chris
C
Sander
Department of Systems Biology, Harvard Medical School, Harvard University, Boston, MA 02115, USA. Electronic address: debbie@hms.harvard.edu.
Debora S
DS
Marks
D019020:Directed Molecular Evolution / Q000379:methods; D023281:Genomics; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000737:chemistry* / Q000235:genetics; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D020543:Proteome / Q000737:chemistry / Q000235:genetics
D064267:Intrinsically Disordered Proteins; D020543:Proteome
EVfold; Evolutionary couplings; bioinformatics; computational biology; conformational flexibility; disorder; maximum entropy; statistical physics; structure prediction
J Cell Comp Physiol. 1959 Dec;54:245-58
14411189
J Cell Sci. 2006 Feb 15;119(Pt 4):615-23
16467570
Cell. 2015 May 21;161(5):1230-1230.e1
26000490
J Mol Biol. 2004 May 14;338(5):1015-26
15111064
Nature. 1994 Apr 21;368(6473):756-60
8152488
Cell. 2013 Nov 21;155(5):1049-60
24267890
Structure. 2005 Jul;13(7):943-4
16004865
Nucleic Acids Res. 2014 Jul;42(Web Server issue):W337-43
24799431
Nucleic Acids Res. 2000 Jan 1;28(1):235-42
10592235
Annu Rev Cell Dev Biol. 2014;30:39-58
25288112
J Biol Chem. 2006 Jan 27;281(4):1853-6
16301309
Cell. 2015 Oct 22;163(3):620-8
26456111
Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):17772-7
19008353
Nature. 2015 Mar 5;519(7541):106-9
25533957
Biochemistry. 2008 Nov 25;47(47):12346-56
18954090
Mol Biol Evol. 2010 Mar;27(3):609-21
19923193
Elife. 2014 Sep 25;3:null
25255213
Nat Rev Mol Cell Biol. 2015 Jan;16(1):18-29
25531225
Proc Natl Acad Sci U S A. 2009 Dec 15;106(50):21149-54
19923431
Elife. 2014 May 01;3:e02030
24842992
Cell. 2012 Jun 22;149(7):1607-21
22579045
Science. 2014 May 9;344(6184):1250494
24812405
Proteins. 2011 Aug;79(8):2380-8
21638331
Nucleic Acids Res. 2016 Jan 4;44(D1):D279-85
26673716
Science. 2006 Apr 14;312(5771):273-6
16614225
Nucleic Acids Res. 2007 Jan;35(Database issue):D786-93
17145717
Nature. 1996 Jul 25;382(6589):325-31
8684460
Biochim Biophys Acta. 2010 Jun;1804(6):1231-64
20117254
Nature. 1970 Nov 21;228(5273):726-39
5528785
Biochemistry. 2004 Jul 13;43(27):8725-34
15236581
Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):905-21
9757107
J Mol Biol. 1963 Apr;6:306-29
13936070
Nat Rev Mol Cell Biol. 2014 Jun;15(6):384-96
24854788
Proc Natl Acad Sci U S A. 2011 Dec 6;108(49):E1293-301
22106262
Nucleic Acids Res. 2013 Jan;41(Database issue):D508-16
23203878
Nat Struct Mol Biol. 2007 Aug;14(8):738-45
17660831
Cell. 2012 May 11;149(4):753-67
22579281
Nature. 2013 Jun 20;498(7454):390-4
23783631
Neurotoxicology. 2002 Oct;23(4-5):527-36
12428725
Nature. 2005 Sep 8;437(7056):266-9
16148936
J Am Chem Soc. 2015 Jan 14;137(1):22-5
25415595
Angew Chem Int Ed Engl. 2014 Apr 14;53(16):4227-30
24623599
Protein Eng. 1995 Sep;8(9):865-71
8746724
Proteins. 2012 Feb;80(2):556-72
22095648
BMC Bioinformatics. 2010 Aug 18;11:431
20718988
Science. 2009 Apr 10;324(5924):203-7
19359577
Trends Biochem Sci. 2008 Jan;33(1):2-8
18054235
Bioinformatics. 2005 Aug 15;21(16):3433-4
15955779
Chem Rev. 2014 Jul 9;114(13):6589-631
24773235
J Biol Chem. 2007 Sep 28;282(39):28874-83
17636256
Nat Struct Mol Biol. 2010 Nov;17(11):1337-42
20953181
Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5762-7
18391200
Proc Natl Acad Sci U S A. 2013 Dec 17;110(51):20533-8
24297889
J Am Chem Soc. 2010 Jun 30;132(25):8657-68
20524659
Elife. 2014 Dec 08;3:e04120
25486594
Phys Rev E Stat Nonlin Soft Matter Phys. 2013 Jan;87(1):012707
23410359
Nat Rev Mol Cell Biol. 2009 Oct;10(10):659-71
19773779
Mol Cell. 2004 Apr 9;14(1):127-38
15068809
Nature. 2014 Apr 17;508(7496):331-9
24740064
Cell. 2015 Aug 27;162(5):1066-77
26317470
Mol Cell. 2001 Sep;8(3):633-44
11583625
Mol Cell. 2009 Aug 14;35(3):280-90
19683493
Biochemistry. 1994 Sep 20;33(37):11079-86
7727360
Cell. 2016 May 5;165(4):963-75
27087444
Proc Natl Acad Sci U S A. 2011 Jul 26;108(30):12283-8
21730181
Nucleic Acids Res. 2008 Aug;36(14):4719-26
18632762
Methods Mol Biol. 2012;796:385-98
22052502
PLoS One. 2011;6(12):e28766
22163331
Nucleic Acids Res. 2015 Jan;43(Database issue):D204-12
25348405
Proc Natl Acad Sci U S A. 2015 Jul 14;112(28):8596-601
26124101
Trends Biochem Sci. 2002 Oct;27(10):527-33
12368089