NR AKIV
AU Salmona,M.; Malesani,P.; de Gioia,L.; Gorla,S.; Bruschi,M.; Molinari,A.; Della Vedova,F.; Pedrotti,B.; Marrari,M.A.; Awan,T.; Bugiani,O.; Forloni,G.; Tagliavini,F.
TI Molecular determinants of the physicochemical properties of a critical prion protein region comprising residues 106-126
QU Biochemical Journal 1999 Aug 15; 342(1): 207-14
PT journal article
AB Prion diseases are marked by the cerebral accumulation of conformationally modified forms of the cellular prion protein (PrPc), known as PrPres. The region comprising the residues 106-126 of human PrP seems to have a key role in this conformational conversion, because a synthetic peptide homologous with this sequence (PrP106-126) adopts different secondary structures in different environments. To investigate the molecular determinants of the physicochemical characteristics of PrP106-126, we synthesized a series of analogues including PrP106-126 H(D), PrP106-126 A and PrP106-126 K, with l-His -> d-His, His -> Ala and His -> Lys substitutions respectively at position 111, PrP106-126 NH(2) with amidation of the C-terminus, PrP106-126 V with an Ala -> Val substition at position 117, and PrP106-126 VNH(2) with an Ala -> Val substitution at position 117 and amidation of the C-terminus. The analysis of the secondary structure and aggregation properties of PrP106-126 and its analogues showed the following. (1) His(111) is central to the conformational changes of PrP peptides. (2) Amidation of the C-terminal Gly(126) yields a predominantly random coil structure, abolishes the molecular polymorphism and decreases the propensity of PrP106-126 to generate amyloid fibrils. (3) PrP106-126 V, carrying an Ala -> Val substitution at position 117, does not demonstrate a fibrillogenic ability superior to that of PrP106-126. However, the presence of Val at position 117 increases the aggregation properties of the amidated peptide. (4) Amyloid fibrils are not required for neurotoxicity because the effects of PrP106-126 NH(2) on primary neuronal cultures were similar to those of the wild-type sequence. Conversely, astroglial proliferation is related to the presence of amyloid fibrils, suggesting that astrogliosis in prion encephalopathies without amyloid deposits is a mediated effect rather than a direct effect of disease-specific PrP isoforms.
MH Amides/metabolism; Amino Acid Sequence; Amino Acid Substitution; Animal; Astrocytes/cytology/drug effects; Cell Division/drug effects; Cell Survival/drug effects; Cells, Cultured; Circular Dichroism; Electrostatics; Gerstmann-Sträussler-Scheinker Disease/genetics; Human; Hydrogen-Ion Concentration; Models, Molecular; Molecular Sequence Data; Neurons/cytology/drug effects; Peptide Fragments/*chemistry/genetics/*metabolism/pharmacology; Polymorphism (Genetics); Prions/*chemistry/genetics/*metabolism/pharmacology; Protein Binding; Protein Structure, Secondary; Rats; Senile Plaques/metabolism/ultrastructure; Support, Non-U.S. Gov't
AD Istituto di Ricerche Farmacologiche 'Mario Negri', Via Eritrea 62, 20157 Milano, Italy. salmona@irfmn.mnegri.it
SP englisch
PO England