title: The mechanism of binding of the KIX domain to the mixed lineage leukemia protein and its allosteric role in the recognition of c-Myb.
abstract: The KIX domain is a mediator of the interaction between different transcription factors. This complex function is carried out via two distinct binding sites located on opposite sides of the protein; namely, the 'c-Myb site' and the 'MLL site', named after their characteristic ligands-the transactivation domain of c-Myb and the mixed lineage leukemia protein (MLL). Both these ligands are unstructured in isolation and fold only upon binding, posing the KIX domain as an ideal candidate to explore the binding induced folding reaction of intrinsically unstructured proteins. Here, we complement the recent kinetic description on the interaction between KIX and c-Myb, by characterizing the binding kinetics between KIX and MLL, at different pH and ionic strength conditions. Furthermore, we analyze quantitatively the mechanism of allosteric communication between the topologically distinct c-Myb and MLL sites. The implications of our results are discussed in the light of previous work on other intrinsically unstructured systems.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti and Istituto di Biologia e Patologia Molecolari del CNR, Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza Università di Roma, 00185, Rome, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Toto
authors.forename: Rajanish
authors.initials: R
authors.lastname: Giri
authors.forename: Maurizio
authors.initials: M
authors.lastname: Brunori
authors.forename: Stefano
authors.initials: S
authors.lastname: Gianni
mesh_terms: D000818:Animals; D001665:Binding Sites; D050882:CREB-Binding Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism*
chemical_list: D020598:Proto-Oncogene Proteins c-myb; D051788:Myeloid-Lymphoid Leukemia Protein; D050882:CREB-Binding Protein
keywords: folding upon binding; intrinsically disordered proteins; kinetics; reaction mechanism
references.citation: ACS Chem Biol. 2013 Jul 19;8(7):1600-10
references.pmid: 23651431
references.citation: Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10610-4
references.pmid: 7938000
references.citation: J Am Chem Soc. 2009 Mar 4;131(8):3063-8
references.pmid: 19203263
references.citation: J Mol Biol. 1992 Apr 5;224(3):771-82
references.pmid: 1569556
references.citation: Phys Chem Chem Phys. 2014 Apr 14;16(14):6323-31
references.pmid: 24317797
references.citation: Biochemistry. 2009 Mar 17;48(10):2115-24
references.pmid: 19220000
references.citation: Curr Opin Struct Biol. 2008 Dec;18(6):756-64
references.pmid: 18952168
references.citation: Biochim Biophys Acta. 2010 Jun;1804(6):1231-64
references.pmid: 20117254
references.citation: J Mol Biol. 2006 Feb 3;355(5):1005-13
references.pmid: 16253272
references.citation: Nucleic Acids Res. 2014 Feb;42(4):2112-25
references.pmid: 24253305
references.citation: Cell. 1997 Dec 12;91(6):741-52
references.pmid: 9413984
references.citation: J Mol Biol. 2004 Mar 26;337(3):521-34
references.pmid: 15019774
references.citation: Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):14942-7
references.pmid: 23980173
references.citation: J Biol Chem. 2002 Nov 8;277(45):43168-74
references.pmid: 12205094
references.citation: Proc Natl Acad Sci U S A. 2013 Aug 27;110(35):14237-42
references.pmid: 23940332
references.citation: FEBS Lett. 2005 Jun 13;579(15):3346-54
references.pmid: 15943980
references.citation: Genes Dev. 2000 Jul 1;14(13):1553-77
references.pmid: 10887150
references.citation: J Biol Chem. 2012 Oct 5;287(41):34316-24
references.pmid: 22915588
references.citation: ACS Chem Biol. 2009 Dec 18;4(12):1017-27
references.pmid: 19821614
references.citation: Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7884-8
references.pmid: 7689231
references.citation: Nature. 1997 Apr 10;386(6625):569-77
references.pmid: 9121580
references.citation: Biochem Biophys Res Commun. 2012 Nov 16;428(2):205-9
references.pmid: 23026051
references.citation: J Am Chem Soc. 2008 Aug 27;130(34):11477-85
references.pmid: 18681437
references.citation: Trends Biochem Sci. 2005 May;30(5):235-9
references.pmid: 15896740
references.citation: J Am Chem Soc. 2013 Jan 30;135(4):1415-22
references.pmid: 23301700
references.citation: J Mol Biol. 1965 May;12:88-118
references.pmid: 14343300