title: Demonstration of a folding after binding mechanism in the recognition between the measles virus NTAIL and X domains.
abstract: In the past decade, a wealth of experimental data has demonstrated that a large fraction of proteins, while functional, are intrinsically disordered at physiological conditions. Many intrinsically disordered proteins (IDPs) undergo a disorder-to-order transition upon binding to their biological targets, a phenomenon known as induced folding. Induced folding may occur through two extreme mechanisms, namely conformational selection and folding after binding. Although the pre-existence of ordered structures in IDPs is a prerequisite for conformational selection, it does not necessarily commit to this latter mechanism, and kinetic studies are needed to discriminate between the two possible scenarios. So far, relatively few studies have addressed this issue from an experimental perspective. Here, we analyze the interaction kinetics between the intrinsically disordered C-terminal domain of the measles virus nucleoprotein (NTAIL) and the X domain (XD) of the viral phosphoprotein. Data reveal that NTAIL recognizes XD by first forming a weak encounter complex in a disordered conformation, which is subsequently locked-in by a folding step; i.e., binding precedes folding. The implications of our kinetic results, in the context of previously reported equilibrium data, are discussed. These results contribute to enhancing our understanding of the molecular mechanisms by which IDPs recognize their partners and represent a paradigmatic example of the need of kinetic methods to discriminate between reaction mechanisms.
authors.affiliation: †Aix-Marseille Université, Architecture et Fonction des Macromolécules Biologiques (AFMB), UMR 7257, 13288, Marseille, France.|‡CNRS, AFMB UMR 7257, 13288, Marseille, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Dosnon
authors.affiliation: §Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Scienze Biochimiche "A. Rossi Fanelli" and Istituto di Biologia e Patologia Molecolari del CNR, Sapienza Università di Roma, 00185, Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bonetti
authors.affiliation: §Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Scienze Biochimiche "A. Rossi Fanelli" and Istituto di Biologia e Patologia Molecolari del CNR, Sapienza Università di Roma, 00185, Rome, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Morrone
authors.affiliation: †Aix-Marseille Université, Architecture et Fonction des Macromolécules Biologiques (AFMB), UMR 7257, 13288, Marseille, France.|‡CNRS, AFMB UMR 7257, 13288, Marseille, France.
authors.forename: Jenny
authors.initials: J
authors.lastname: Erales
authors.affiliation: §Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Scienze Biochimiche "A. Rossi Fanelli" and Istituto di Biologia e Patologia Molecolari del CNR, Sapienza Università di Roma, 00185, Rome, Italy.
authors.forename: Eva
authors.initials: E
authors.lastname: di Silvio
authors.affiliation: †Aix-Marseille Université, Architecture et Fonction des Macromolécules Biologiques (AFMB), UMR 7257, 13288, Marseille, France.|‡CNRS, AFMB UMR 7257, 13288, Marseille, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Longhi
authors.affiliation: §Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Scienze Biochimiche "A. Rossi Fanelli" and Istituto di Biologia e Patologia Molecolari del CNR, Sapienza Università di Roma, 00185, Rome, Italy.|∥Department of Chemistry, University of Cambridge, Cambridge CB21EW, United Kingdom.
authors.forename: Stefano
authors.initials: S
authors.lastname: Gianni
mesh_terms: D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D064267:Intrinsically Disordered Proteins / Q000737:chemistry* / Q000235:genetics; D007700:Kinetics; D008459:Measles virus / Q000737:chemistry*; D008958:Models, Molecular; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins / Q000737:chemistry* / Q000235:genetics; D010750:Phosphoproteins / Q000737:chemistry* / Q000235:genetics; D011485:Protein Binding; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D013816:Thermodynamics; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics
chemical_list: D064267:Intrinsically Disordered Proteins; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins; D010750:Phosphoproteins; D014764:Viral Proteins; C058314:nucleoprotein, Measles virus