title: Molecular Recognition by Templated Folding of an Intrinsically Disordered Protein.
abstract: Intrinsically disordered proteins often become structured upon interacting with their partners. The mechanism of this 'folding upon binding' process, however, has not been fully characterised yet. Here we present a study of the folding of the intrinsically disordered transactivation domain of c-Myb (c-Myb) upon binding its partner KIX. By determining the structure of the folding transition state for the binding of wild-type and three mutational variants of KIX, we found a remarkable plasticity of the folding pathway of c-Myb. To explain this phenomenon, we show that the folding of c-Myb is templated by the structure of KIX. This adaptive folding behaviour, which occurs by heterogeneous nucleation, differs from the robust homogeneous nucleation typically observed for globular proteins. We suggest that this templated folding mechanism may enable intrinsically disordered proteins to achieve specific and reliable binding with multiple partners while avoiding aberrant interactions.
authors.affiliation: Istituto Pasteur - Fondazione Cenci Bolognetti and Istituto di Biologia e Patologia Molecolari del CNR, Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza University of Rome, 00185 Rome, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Toto
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Carlo
authors.initials: C
authors.lastname: Camilloni
authors.affiliation: Istituto Pasteur - Fondazione Cenci Bolognetti and Istituto di Biologia e Patologia Molecolari del CNR, Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza University of Rome, 00185 Rome, Italy.
authors.forename: Rajanish
authors.initials: R
authors.lastname: Giri
authors.affiliation: Istituto Pasteur - Fondazione Cenci Bolognetti and Istituto di Biologia e Patologia Molecolari del CNR, Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza University of Rome, 00185 Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Brunori
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
authors.affiliation: Istituto Pasteur - Fondazione Cenci Bolognetti and Istituto di Biologia e Patologia Molecolari del CNR, Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza University of Rome, 00185 Rome, Italy.|Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Stefano
authors.initials: S
authors.lastname: Gianni
mesh_terms: D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D064267:Intrinsically Disordered Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D020598:Proto-Oncogene Proteins c-myb / Q000737:chemistry / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D002352:Carrier Proteins; D064267:Intrinsically Disordered Proteins; D020598:Proto-Oncogene Proteins c-myb