title: Structural transitions in full-length human prion protein detected by xenon as probe and spin labeling of the N-terminal domain.
abstract: Fatal neurodegenerative disorders termed transmissible spongiform encephalopathies (TSEs) are associated with the accumulation of fibrils of misfolded prion protein PrP. The noble gas xenon accommodates into four transiently enlarged hydrophobic cavities located in the well-folded core of human PrP(23-230) as detected by [(1)H, (15)N]-HSQC spectroscopy. In thermal equilibrium a fifth xenon binding site is formed transiently by amino acids A120 to L125 of the presumably disordered N-terminal domain and by amino acids K185 to T193 of the well-folded domain. Xenon bound PrP was modelled by restraint molecular dynamics. The individual microscopic and macroscopic dissociation constants could be derived by fitting the data to a model including a dynamic opening and closing of the cavities. As observed earlier by high pressure NMR spectroscopy xenon binding influences also other amino acids all over the N-terminal domain including residues of the AGAAAAGA motif indicating a structural coupling between the N-terminal domain and the core domain. This is in agreement with spin labelling experiments at positions 93 or 107 that show a transient interaction between the N-terminus and the start of helix 2 and the end of helix 3 of the core domain similar to that observed earlier by Zn(2+)-binding to the octarepeat motif.
authors.affiliation: Institute of Biophysics and Physical Biochemistry and Centre of Magnetic Resonance in Chemistry and Biomedicine (CMRCB), University of Regensburg, 93040 Regensburg, Germany.
authors.forename: Sunilkumar Puthenpurackal
authors.initials: SP
authors.lastname: Narayanan
authors.affiliation: Institute of Biophysics and Physical Biochemistry and Centre of Magnetic Resonance in Chemistry and Biomedicine (CMRCB), University of Regensburg, 93040 Regensburg, Germany.
authors.forename: Divya Gopalakrishnan
authors.initials: DG
authors.lastname: Nair
authors.affiliation: Research Center for Bio-Macromolecules and Department of Biopolymers, NW1/BGI, University of Bayreuth, 95447 Bayreuth, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schaal
authors.affiliation: Institute of Biophysics and Physical Biochemistry and Centre of Magnetic Resonance in Chemistry and Biomedicine (CMRCB), University of Regensburg, 93040 Regensburg, Germany.
authors.forename: Marisa
authors.initials: M
authors.lastname: Barbosa de Aguiar
authors.affiliation: Research Center for Bio-Macromolecules and Department of Biopolymers, NW1/BGI, University of Bayreuth, 95447 Bayreuth, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Wenzel
authors.affiliation: Institute of Biophysics and Physical Biochemistry and Centre of Magnetic Resonance in Chemistry and Biomedicine (CMRCB), University of Regensburg, 93040 Regensburg, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Kremer
authors.affiliation: Research Center for Bio-Macromolecules and Department of Biopolymers, NW1/BGI, University of Bayreuth, 95447 Bayreuth, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Schwarzinger
authors.affiliation: Institute of Biophysics and Physical Biochemistry and Centre of Magnetic Resonance in Chemistry and Biomedicine (CMRCB), University of Regensburg, 93040 Regensburg, Germany.
authors.forename: Hans Robert
authors.initials: HR
authors.lastname: Kalbitzer
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D000072002:Prion Proteins / Q000737:chemistry*; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D017434:Protein Structure, Tertiary; D013113:Spin Labels; D014978:Xenon / Q000737:chemistry*
chemical_list: D000072002:Prion Proteins; D013113:Spin Labels; D014978:Xenon