title: Structure of the transition state for the binding of c-Myb and KIX highlights an unexpected order for a disordered system.
abstract: A classical dogma of molecular biology dictates that the 3D structure of a protein is necessary for its function. However, a considerable fraction of the human proteome, although functional, does not adopt a defined folded state under physiological conditions. These intrinsically disordered proteins tend to fold upon binding to their partners with a molecular mechanism that is elusive to experimental characterization. Indeed, although many hypotheses have been put forward, the functional role (if any) of disorder in these intrinsically denatured systems is still shrouded in mystery. Here, we characterize the structure of the transition state of the binding-induced folding in the reaction between the KIX domain of the CREB-binding protein and the transactivation domain of c-Myb. The analysis, based on the characterization of a series of conservative site-directed mutants, reveals a very high content of native-like structure in the transition state and indicates that the recognition between KIX and c-Myb is geometrically precise. The implications of our results in the light of previous work on intrinsically unstructured systems are discussed.
authors: Istituto Pasteur-Fondazione Cenci Bolognetti and Istituto di Biologia e Patologia Molecolari del Consiglio Nazionale delle Ricerche, Dipartimento di Scienze Biochimiche A. Rossi Fanelli, Sapienza Università di Roma, 00185 Rome, Italy.
authors: Rajanish
authors: R
authors: Giri
authors: Angela
authors: A
authors: Morrone
authors: Angelo
authors: A
authors: Toto
authors: Maurizio
authors: M
authors: Brunori
authors: Stefano
authors: S
authors: Gianni
mesh_terms: D055592:Biophysical Phenomena; D050882:CREB-Binding Protein / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D020598:Proto-Oncogene Proteins c-myb / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D064267:Intrinsically Disordered Proteins; D020598:Proto-Oncogene Proteins c-myb; D011994:Recombinant Proteins; D050882:CREB-Binding Protein
keywords: kinetics; mutagenesis; protein folding
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