Inferring interaction partners from protein sequences.
Specific protein-protein interactions are crucial in the cell, both to ensure the formation and stability of multiprotein complexes and to enable signal transduction in various pathways. Functional interactions between proteins result in coevolution between the interaction partners, causing their sequences to be correlated. Here we exploit these correlations to accurately identify, from sequence data alone, which proteins are specific interaction partners. Our general approach, which employs a pairwise maximum entropy model to infer couplings between residues, has been successfully used to predict the 3D structures of proteins from sequences. Thus inspired, we introduce an iterative algorithm to predict specific interaction partners from two protein families whose members are known to interact. We first assess the algorithm's performance on histidine kinases and response regulators from bacterial two-component signaling systems. We obtain a striking 0.93 true positive fraction on our complete dataset without any a priori knowledge of interaction partners, and we uncover the origin of this success. We then apply the algorithm to proteins from ATP-binding cassette (ABC) transporter complexes, and obtain accurate predictions in these systems as well. Finally, we present two metrics that accurately distinguish interacting protein families from noninteracting ones, using only sequence data.
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544; Department of Physics, Princeton University, Princeton, NJ 08544; Sorbonne Universités, Université Pierre et Marie Curie - Paris 6, CNRS, Laboratoire Jean Perrin, UMR 8237, F-75005 Paris, France; wingreen@princeton.edu anne-florence.bitbol@upmc.fr ljc37@cam.ac.uk.
Anne-Florence
AF
Bitbol
Department of Molecular Biology, Princeton University, Princeton, NJ 08544.
Robert S
RS
Dwyer
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom wingreen@princeton.edu anne-florence.bitbol@upmc.fr ljc37@cam.ac.uk.
Lucy J
LJ
Colwell
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544; Department of Molecular Biology, Princeton University, Princeton, NJ 08544; wingreen@princeton.edu anne-florence.bitbol@upmc.fr ljc37@cam.ac.uk.
Ned S
NS
Wingreen
D018528:ATP-Binding Cassette Transporters / Q000737:chemistry* / Q000235:genetics; D000465:Algorithms; D001419:Bacteria / Q000737:chemistry / Q000235:genetics; D019277:Entropy; D000071677:Histidine Kinase / Q000737:chemistry* / Q000235:genetics; D011485:Protein Binding / Q000235:genetics*; D060066:Protein Interaction Maps / Q000235:genetics*; D020539:Sequence Analysis, Protein; D015398:Signal Transduction
D018528:ATP-Binding Cassette Transporters; D000071677:Histidine Kinase
coevolution; direct coupling analysis; maximum entropy; paralogs; protein−protein interactions
PLoS One. 2014 Mar 24;9(3):e92721
24663061
Nature. 2006 Apr 20;440(7087):1007-12
16625187
PLoS Comput Biol. 2014 Aug 07;10(8):e1003776
25102049
PLoS One. 2011 May 09;6(5):e19729
21573011
Proc Natl Acad Sci U S A. 2012 Jun 26;109(26):10340-5
22691493
Annu Rev Genet. 2007;41:121-45
18076326
Immunity. 2013 Mar 21;38(3):606-17
23521886
Elife. 2014 Sep 25;3:null
25255213
Nat Biotechnol. 2014 Mar;32(3):285-90
24561554
Elife. 2014 May 01;3:e02030
24842992
Mol Syst Biol. 2008;4:165
18277381
Nucleic Acids Res. 2016 Jan 4;44(D1):D279-85
26673716
J Mol Biol. 1987 Feb 20;193(4):693-707
3612789
BMC Genomics. 2009 Jul 15;10:315
19604365
PLoS One. 2016 Feb 16;11(2):e0149166
26882169
Cell. 2009 Oct 16;139(2):325-36
19800110
Proc Natl Acad Sci U S A. 2011 Dec 6;108(49):E1293-301
22106262
Proc Natl Acad Sci U S A. 2012 Mar 27;109(13):4786-91
22427355
PLoS Comput Biol. 2016 May 13;12(5):e1004889
27177270
Nucleic Acids Res. 2015 Jan;43(Database issue):D536-41
25324303
Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5405-10
20212159
Nat Rev Mol Cell Biol. 2009 Mar;10(3):218-27
19234479
Cell. 2008 Jun 13;133(6):1043-54
18555780
Proc Natl Acad Sci U S A. 2012 Jul 24;109(30):12254-9
22773816
Proc Natl Acad Sci U S A. 2006 Dec 12;103(50):19033-8
17138668
Genetics. 2013 Oct;195(2):443-55
23934888
Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):67-72
19116270
Phys Rev E Stat Nonlin Soft Matter Phys. 2013 Jan;87(1):012707
23410359
Science. 1999 Oct 8;286(5438):295-9
10514373
Bioinformatics. 2012 Jan 15;28(2):184-90
22101153
Proc Natl Acad Sci U S A. 2014 Feb 4;111(5):E563-71
24449878
Mol Biol Evol. 2016 Jan;33(1):268-80
26446903
PLoS One. 2011;6(12):e28766
22163331