title: Binding of disordered proteins to a protein hub.
abstract: A small number of proteins, called hubs, have high connectivity and are essential for interactome functionality and integrity. Keap1 is a crucial hub in the oxidative stress response and apoptosis. The Kelch domain of Keap1 preferentially binds to disordered regions of its partners, which share similar binding motifs, but have a wide range of binding affinities. Isothermal titration calorimetry (ITC) and multi-microsecond molecular dynamics (MD) simulations were used to determine the factors that govern the affinity of all currently known disordered binding partners to Kelch. Our results show that the affinities to this hub are largely determined by the extent of preformed bound state-like conformation in the free state structures of these disordered targets. Based on our findings, we have designed a high-affinity peptide that can specifically disrupt the Keap1-NRF2 interaction and has the potential for therapeutic applications.
authors.affiliation: Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada N6A 5C1.
authors.forename: Elio A
authors.initials: EA
authors.lastname: Cino
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Killoran
authors.forename: Mikko
authors.initials: M
authors.lastname: Karttunen
authors.forename: Wing-Yiu
authors.initials: WY
authors.lastname: Choy
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D064267:Intrinsically Disordered Proteins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D056510:Position-Specific Scoring Matrices; D011487:Protein Conformation; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D016415:Sequence Alignment; D013816:Thermodynamics
chemical_list: D064267:Intrinsically Disordered Proteins; D010455:Peptides
references.citation: J Comput Chem. 2004 Oct;25(13):1605-12
references.pmid: 15264254
references.citation: J Biol Chem. 2009 May 15;284(20):13856-13868
references.pmid: 19279002
references.citation: Genome Biol. 2006;7(6):R45
references.pmid: 16780599
references.citation: Mol Cell Biol. 2006 Apr;26(8):2887-900
references.pmid: 16581765
references.citation: Acta Crystallogr Sect F Struct Biol Cryst Commun. 2008 Apr 1;64(Pt 4):233-8
references.pmid: 18391415
references.citation: J Mol Biol. 2006 Oct 6;362(5):1043-59
references.pmid: 16935303
references.citation: J Chem Phys. 2007 Jan 7;126(1):014101
references.pmid: 17212484
references.citation: J Struct Biol. 2011 Nov;176(2):133-42
references.pmid: 21820058
references.citation: Nat Rev Cancer. 2012 Jul 19;12(8):564-71
references.pmid: 22810811
references.citation: PLoS One. 2012;7(4):e35122
references.pmid: 22558124
references.citation: Biochem Biophys Res Commun. 2011 Apr 15;407(3):501-6
references.pmid: 21414291
references.citation: Int J Nephrol. 2012;2012:321714
references.pmid: 22701794
references.citation: Biophys J. 2013 Mar 19;104(6):L12-4
references.pmid: 23528098
references.citation: Nat Protoc. 2007;2(11):2728-33
references.pmid: 18007608
references.citation: J Chem Theory Comput. 2008 Mar;4(3):435-47
references.pmid: 26620784
references.citation: Cell Death Differ. 2011 Mar;18(3):439-51
references.pmid: 20865015
references.citation: Eur Biophys J. 2005 Jun;34(4):273-84
references.pmid: 15803330
references.citation: Bioinformatics. 2007 Nov 1;23(21):2947-8
references.pmid: 17846036
references.citation: Biochemistry. 2007 Nov 13;46(45):13120-30
references.pmid: 17929838
references.citation: J Mol Biol. 2004 May 14;338(5):1015-26
references.pmid: 15111064
references.citation: Mol Biosyst. 2012 Jan;8(1):268-81
references.pmid: 21909575
references.citation: J Mol Graph. 1996 Feb;14(1):33-8, 27-8
references.pmid: 8744570
references.citation: Sci Signal. 2012 Apr 17;5(220):pe17
references.pmid: 22510467
references.citation: Nat Cell Biol. 2010 Mar;12(3):213-23
references.pmid: 20173742
references.citation: Biochem Biophys Res Commun. 1997 Jul 18;236(2):313-22
references.pmid: 9240432
references.citation: J Phys Chem B. 2013 Jan 10;117(1):118-24
references.pmid: 23205890
references.citation: Cell. 2005 Sep 23;122(6):957-68
references.pmid: 16169070
references.citation: Mol Cell Biol. 2012 Apr;32(8):1506-17
references.pmid: 22331464
references.citation: J Mol Biol. 2007 Sep 14;372(2):549-61
references.pmid: 17681540
references.citation: Mol Cancer Ther. 2004 Jul;3(7):885-93
references.pmid: 15252150
references.citation: Biochim Biophys Acta. 2010 Apr;1804(4):996-1010
references.pmid: 20100603
references.citation: J Chem Theory Comput. 2012 Aug 14;8(8):2725-2740
references.pmid: 22904695
references.citation: J Mol Biol. 1982 May 5;157(1):105-32
references.pmid: 7108955
references.citation: EMBO J. 2006 Aug 9;25(15):3605-17
references.pmid: 16888629
references.citation: Nat Nanotechnol. 2010 Aug;5(8):555-7
references.pmid: 20622865
references.citation: Cancer Lett. 2012 Dec 1;325(1):26-34
references.pmid: 22743616
references.citation: Proteins. 1993 Nov;17(3):232-51
references.pmid: 8272423
references.citation: Free Radic Biol Med. 2012 Jan 15;52(2):444-51
references.pmid: 22107959
references.citation: Cell. 2011 Mar 18;144(6):986-98
references.pmid: 21414488
references.citation: Genome Res. 2004 Jun;14(6):1188-90
references.pmid: 15173120
references.citation: Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3012-7
references.pmid: 11248023
references.citation: Biol Chem. 2006 Oct-Nov;387(10-11):1311-20
references.pmid: 17081101
references.citation: J Nat Prod. 2011 Mar 25;74(3):537-45
references.pmid: 21309592
references.citation: Mol Cell. 2006 Mar 3;21(5):689-700
references.pmid: 16507366
references.citation: J Mol Biol. 1997 Jan 17;265(2):118-27
references.pmid: 9020976
references.citation: Cell Motil Cytoskeleton. 2002 Mar;51(3):147-64
references.pmid: 11921171
references.citation: Genes Dev. 1999 Jan 1;13(1):76-86
references.pmid: 9887101
references.citation: PLoS One. 2011;6(11):e27371
references.pmid: 22125611
references.citation: J Biol Chem. 2006 Dec 8;281(49):37893-903
references.pmid: 17046835
references.citation: Nature. 2004 Jul 1;430(6995):88-93
references.pmid: 15190252
references.citation: J Comput Chem. 2004 Oct;25(13):1656-76
references.pmid: 15264259
references.citation: Free Radic Biol Med. 2011 May 1;50(9):1186-95
references.pmid: 21295136
references.citation: FEBS J. 2005 Oct;272(20):5129-48
references.pmid: 16218947
references.citation: Cell Signal. 2010 Nov;22(11):1645-54
references.pmid: 20600852
references.citation: J Chem Theory Comput. 2012 Aug 14;8(8):2905-11
references.pmid: 26592129
references.citation: Mol Cell Biol. 2007 Nov;27(21):7511-21
references.pmid: 17785452
references.citation: Biochemistry. 2004 Sep 28;43(38):12113-22
references.pmid: 15379550
references.citation: Nature. 2005 Oct 20;437(7062):1173-8
references.pmid: 16189514
references.citation: J Biol Chem. 2012 Feb 24;287(9):6539-50
references.pmid: 22215675