NR AORX
AU Dodson,G.G.; Gamblin,S.J.; Haire,L.M.; Smerdon,S.J.; Nishi,V.; Whyte,S.M.; Gill,A.C.; Dodson,E.J.; Verma,C.; Bayley,P.M.
TI The crystal structure of a truncated sheep prion protein monomer and its relationship to amyloid fibril formation
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Poster session - BR-114
PT Konferenz-Poster
AB
We report the crystal structure at 2Å resolution of the monomeric form of the C-terminal domain of the ARQ allele of the sheep prion protein (PrP), comprising residues 121-230 (human PrP numbering). This globular domain,lacking the unstructured N-terminal octa-peptide repeat region, is known to be neurotoxic in transgenic mice (1). The sheep PrP structure is monomeric, and has distinctive features, including a well-defined phosphate ion bound via electrostatic and hydrogen bond interactions. It corresponds in secondary structure content and organisation to the various mammalian species determined by NMR, and, after allowance for the helix swap, the dimeric form of N-truncated human PrP (2). Analysis of the new structure, in conjunction with observations from the other structural studies, identifies two possible loci within the monomer for the development of beta-sheet driven polymerisation. These loci are first the short beta-structure region of PrP, as seen in nmr structures, and also present in the crystallographic dimer, and secondly, the interstrand region involved in the PrP-PrP interaction as seen in the dimer structure, accompanied by swapping of helix 3. These results suggest a mechanism whereby multiple sites of beta-structure formation within the PrP molecule are collectively involved in the formation of oligomeric and polymeric associated species rich in beta-structure, en route to amyloid fibril formation.
1. Shmerling D, Hegyi I, Fischer M, Blattler T, Brandner S, Gotz J, Rulicke T, Flechsig E, Cozzio A, von Mering C, Hangartner C, Aguzzi A, Weissmann C. Expression of amino-terminally truncated PrP in the mouse leading to ataxia and specific cerebellar lesions. Cell. 93:203-14 (1998).
2. Knaus KJ, Morillas M, Swietnicki W, Malone M, Surewicz WK, Yee VC. Crystal structure of the human prion protein reveals a mechanism for oligomerization : Nat Struct Biol 8:770-4 (2001).
AD Guy G. Dodson, Stephen J. Gamblin, Lesley M. Haire, Stephen J. Smerdon, Vasisht Nishi, Sheena M. Whyte, Division of Protein Structure, N.I.M.R., Mill Hill, London, UK; Andrew C. Gill, Division of TSE's, Institute for Animal Health, Compton, UK; Eleanor J. Dodson, Chandra Verma, York Structural Biology Laboratory, University of York, UK; Peter M. Bayley, Division of Physical Biochemistry, N.I.M.R., Mill Hill, London, UK
SP englisch
PO Deutschland