title: Characterization of the conformational fluctuations in the Josephin domain of ataxin-3.
abstract: As for a variety of other molecular recognition processes, conformational fluctuations play an important role in the cleavage of polyubiquitin chains by the Josephin domain of ataxin-3. The interaction between Josephin and ubiquitin appears to be mediated by the motions of α-helical hairpin that is unusual among deubiquitinating enzymes. Here, we characterized the conformational fluctuations of the helical hairpin by incorporating NMR measurements as replica-averaged restraints in molecular dynamics simulations, and by validating the results by small-angle x-ray scattering measurements. This approach allowed us to define the extent of the helical hairpin motions and suggest a role of such motions in the recognition of ubiquitin.
authors.affiliation: MRC National Institute for Medical Research, London, United Kingdom.
authors.forename: Domenico
authors.initials: D
authors.lastname: Sanfelice
authors.affiliation: Division of Molecular Biosciences, Imperial College London, London, United Kingdom.
authors.forename: Alfonso
authors.initials: A
authors.lastname: De Simone
authors.affiliation: Institute for Research in Biomedicine, 6500 Bellinzona, Switzerland; Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.affiliation: MRC National Institute for Medical Research, London, United Kingdom.
authors.forename: Serena
authors.initials: S
authors.lastname: Faggiano
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
authors.affiliation: Department of Basic and Clinical Neurosciences, King's College London, London, United Kingdom. Electronic address: annalisa.1.pastore@kcl.ac.uk.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pastore
mesh_terms: D000595:Amino Acid Sequence; D000067699:Ataxin-3 / Q000737:chemistry*; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000737:chemistry*; D053838:Scattering, Small Angle; D014961:X-Ray Diffraction
chemical_list: D012097:Repressor Proteins; C092341:ATXN3 protein, human; D000067699:Ataxin-3