title: New insights into the molecular mechanism of amyloid formation from cysteine scanning.
abstract: Our laboratory recently reported the identification of a peptide region, QVNI, within the prion domain of the yeast protein Ure2 that may act as an initiation point for fibril formation.(1) This potential amyloid-forming region, which corresponds to residues 18-21 of Ure2, was initially identified by systematic cysteine scanning of the Ure2 prion domain. The point mutant R17C, and the corresponding octapeptide CQVNIGNR, were found to form fibrils rapidly under oxidative conditions due to the formation of a disulfide bond. Deletions within the QVNI sequence cause the fibril formation ability of R17C Ure2 to be inhibited. The aggregation propensity of this region is strongly modulated by its preceding residue: replacement of R17 with a hydrophobic residue promotes fibril formation in both full-length Ure2 and in the corresponding octapeptides. The wild-type octapeptide, RQVNIGNR, also forms fibrils, and is the shortest amyloid-forming peptide found for Ure2 to date. Interestingly, the wild-type octapeptide crystallizes readily and so provides a starting point towards obtaining high resolution structural information for the amyloid core of Ure2 fibrils.
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. sarah.perrett@cantab.net
authors.forename: Li
authors.initials: L
authors.lastname: Fei
authors.forename: Sarah
authors.initials: S
authors.lastname: Perrett
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism*; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D011328:Prions / Q000737:chemistry / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D000682:Amyloid; D011328:Prions; D029701:Saccharomyces cerevisiae Proteins; D005979:Glutathione Peroxidase; C067020:URE2 protein, S cerevisiae; D003545:Cysteine