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Titolo:
PROLINES AND AMYLOIDOGENICITY IN FRAGMENTS OF THE ALZHEIMERS PEPTIDE BETA A4/
Autore:
WOOD SJ; WETZEL R; MARTIN JD; HURLE MR;
Indirizzi:
SMITHKLINE BEECHAM PHARMACEUT,DEPT MACROMOLEC SCI,709 SWEDELAND RD KING OF PRUSSIA PA 19406 SMITHKLINE BEECHAM PHARMACEUT,DEPT MACROMOLEC SCI KING OF PRUSSIA PA 19406
Titolo Testata:
Biochemistry
fascicolo: 3, volume: 34, anno: 1995,
pagine: 724 - 730
SICI:
0006-2960(1995)34:3<724:PAAIFO>2.0.ZU;2-J
Fonte:
ISI
Lingua:
ENG
Soggetto:
X-RAY-DIFFRACTION; AMYLOID FIBRIL FORMATION; PRION PROTEIN; SYSTEMIC AMYLOIDOSIS; SECONDARY STRUCTURE; CIRCULAR-DICHROISM; SYNTHETIC PEPTIDES; INVITRO FORMATION; CARBOXY TERMINUS; BETA-A4 PEPTIDES;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
81
Recensione:
Indirizzi per estratti:
Citazione:
S.J. Wood et al., "PROLINES AND AMYLOIDOGENICITY IN FRAGMENTS OF THE ALZHEIMERS PEPTIDE BETA A4/", Biochemistry, 34(3), 1995, pp. 724-730

Abstract

Although it is well accepted that the structure of amyloid fibrils isdominated by some form of antiparallel beta-sheet, there are few details on the secondary structural arrangements of the constituent peptides and how these peptides pack together in the fibril. We describe here the use of scanning proline mutagenesis to map the secondary structural roles of each residue in amyloidogenic peptide fragments of the Alzheimer's amyloid peptide beta/A4. In two series of fragments related to residues 15-23 and 12-26 of beta/A4, we show that Pro replacement of any residue in the amyloidogenic sequence LVFFAED, corresponding to residues 17-23, leads to essentially complete loss of fibril formationand to excellent peptide solubility. Since peptidyl-prolyl bonds are incapable of forming standard extended chain conformations, the results suggest that residues 17-23 make up the beta-sheet core of the fibrils formed by these fragments. In contrast to the proline replacements,alanine substitutions at residues 17, 18, and 20 have no effect on fibril formation, while replacement of Phe(19) reduces fibril formation to 15% of the level found for the wild type sequence. Scanning prolinemutagenesis should play a useful role in mapping the secondary structural features of larger amyloidogenic peptide sequences, including longer, physiologically relevant forms of beta/A4. In addition, these results suggest explanations for some amyloidogenic effects observed in disease-related peptides and also suggest a possible role for aggregation-inhibiting insertion of prolines in protein evolution and protein design.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 21/09/20 alle ore 19:07:56