title: Conformational propensities of intrinsically disordered proteins influence the mechanism of binding and folding.
abstract: Intrinsically disordered proteins (IDPs) frequently function in protein interaction networks that regulate crucial cellular signaling pathways. Many IDPs undergo transitions from disordered conformational ensembles to folded structures upon binding to their cellular targets. Several possible binding mechanisms for coupled folding and binding have been identified: folding of the IDP after association with the target ("induced fit"), or binding of a prefolded state in the conformational ensemble of the IDP to the target protein ("conformational selection"), or some combination of these two extremes. The interaction of the intrinsically disordered phosphorylated kinase-inducible domain (pKID) of the cAMP-response element binding (CREB) protein with the KIX domain of a general transcriptional coactivator CREB-binding protein (CBP) provides an example of the induced-fit mechanism. Here we show by NMR relaxation dispersion experiments that a different intrinsically disordered ligand, the transactivation domain of the transcription factor c-Myb, interacts with KIX at the same site as pKID but via a different binding mechanism that involves elements of conformational selection and induced fit. In contrast to pKID, the c-Myb activation domain has a strong propensity for spontaneous helix formation in its N-terminal region, which binds to KIX in a predominantly folded conformation. The C-terminal region of c-Myb exhibits a much smaller helical propensity and likely folds via an induced-fit process after binding to KIX. We propose that the intrinsic secondary structure propensities of pKID and c-Myb determine their binding mechanisms, consistent with their functions as inducible and constitutive transcriptional activators.
authors.affiliation: Department of Integrative Structural and Computational Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037; Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Meguro, Tokyo 153-8902, Japan; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.
authors.forename: Munehito
authors.initials: M
authors.lastname: Arai
authors.affiliation: Department of Integrative Structural and Computational Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Kenji
authors.initials: K
authors.lastname: Sugase
authors.affiliation: Department of Integrative Structural and Computational Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: H Jane
authors.identifier: http://orcid.org/0000-0001-6855-3398
authors.initials: HJ
authors.lastname: Dyson
authors.affiliation: Department of Integrative Structural and Computational Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037; wright@scripps.edu.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Wright
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000737:chemistry / Q000378:metabolism; D002151:Calorimetry; D064267:Intrinsically Disordered Proteins / Q000737:chemistry* / Q000378:metabolism*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D020598:Proto-Oncogene Proteins c-myb / Q000737:chemistry / Q000378:metabolism
chemical_list: D064267:Intrinsically Disordered Proteins; D020598:Proto-Oncogene Proteins c-myb; D050882:CREB-Binding Protein
keywords: NMR relaxation; coupled folding and binding; intrinsically disordered protein; transcriptional activator c-Myb; transcriptional coactivator CBP