Molecular determinants of the physicochemical properties of a critical prion protein region comprising residues 106-126

Mario Salmona, Paolo Malesani, Luca De Gioia, Stefano Gorla, Maurizio Bruschi, Antonio Molinari, Franco Della Vedova, Barbara Pedrotti, Maria Anna Marrari, Tazeen Awan, Orso Bugiani, Gianluigi Forloni, Fabrizio Tagliavini

Research output: Contribution to journalArticle

Abstract

Prion diseases are marked by the cerebral accumulation of conformationally modified forms of the cellular prion protein (PrP(c)), known as PrP(res). 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 NH2 with amidation of the C-terminus, PrP106-126 V with an Ala → Val substition at position 117, and PrP106-126 VNH2 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) His111 is central to the conformational changes of PrP peptides. (2) Amidation of the C-terminal Gly126 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 NH2 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.

Original languageEnglish
Pages (from-to)207-214
Number of pages8
JournalBiochemical Journal
Volume342
Issue number1
DOIs
Publication statusPublished - Aug 15 1999

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Amyloid
Peptides
Substitution reactions
Prions
PrPSc Proteins
Prion Diseases
Agglomeration
Amyloid Plaques
Brain Diseases
Sequence Homology
Molecular Structure
Protein Isoforms
Polymorphism
Deposits
Prion Proteins

Keywords

  • Amyloid
  • Prion protein peptides
  • Secondary structure modifications

ASJC Scopus subject areas

  • Biochemistry

Cite this

Molecular determinants of the physicochemical properties of a critical prion protein region comprising residues 106-126. / Salmona, Mario; Malesani, Paolo; De Gioia, Luca; Gorla, Stefano; Bruschi, Maurizio; Molinari, Antonio; Della Vedova, Franco; Pedrotti, Barbara; Marrari, Maria Anna; Awan, Tazeen; Bugiani, Orso; Forloni, Gianluigi; Tagliavini, Fabrizio.

In: Biochemical Journal, Vol. 342, No. 1, 15.08.1999, p. 207-214.

Research output: Contribution to journalArticle

Salmona, M, Malesani, P, De Gioia, L, Gorla, S, Bruschi, M, Molinari, A, Della Vedova, F, Pedrotti, B, Marrari, MA, Awan, T, Bugiani, O, Forloni, G & Tagliavini, F 1999, 'Molecular determinants of the physicochemical properties of a critical prion protein region comprising residues 106-126', Biochemical Journal, vol. 342, no. 1, pp. 207-214. https://doi.org/10.1042/0264-6021:3420207
Salmona, Mario ; Malesani, Paolo ; De Gioia, Luca ; Gorla, Stefano ; Bruschi, Maurizio ; Molinari, Antonio ; Della Vedova, Franco ; Pedrotti, Barbara ; Marrari, Maria Anna ; Awan, Tazeen ; Bugiani, Orso ; Forloni, Gianluigi ; Tagliavini, Fabrizio. / Molecular determinants of the physicochemical properties of a critical prion protein region comprising residues 106-126. In: Biochemical Journal. 1999 ; Vol. 342, No. 1. pp. 207-214.
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AU - Bruschi, Maurizio

AU - Molinari, Antonio

AU - Della Vedova, Franco

AU - Pedrotti, Barbara

AU - Marrari, Maria Anna

AU - Awan, Tazeen

AU - Bugiani, Orso

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