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Titolo:
Role of the single disulphide bond of beta(2)-microglobulin in amyloidosisin vitro
Autore:
Smith, DP; Radford, SE;
Indirizzi:
Univ Leeds, Sch Biochem & Mol Biol, Leeds LS2 9JT, W Yorkshire, England Univ Leeds Leeds W Yorkshire England LS2 9JT S2 9JT, W Yorkshire, England
Titolo Testata:
PROTEIN SCIENCE
fascicolo: 9, volume: 10, anno: 2001,
pagine: 1775 - 1784
SICI:
0961-8368(200109)10:9<1775:ROTSDB>2.0.ZU;2-K
Fonte:
ISI
Lingua:
ENG
Soggetto:
X-RAY-DIFFRACTION; IN-VITRO; FIBRIL FORMATION; PRION PROTEIN; LIGHT-CHAINS; HUMAN BETA-2-MICROGLOBULIN; ELECTRON-MICROSCOPY; AGGREGATION; DEPOSITION; DOMAIN;
Keywords:
beta(2)-microgobulin; amyloidosis; disulphide bond; protein fibril;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
52
Recensione:
Indirizzi per estratti:
Indirizzo: Radford, SE Univ Leeds, Sch Biochem & Mol Biol, Leeds LS2 9JT, W Yorkshire, England Univ Leeds Leeds W Yorkshire England LS2 9JT rkshire, England
Citazione:
D.P. Smith e S.E. Radford, "Role of the single disulphide bond of beta(2)-microglobulin in amyloidosisin vitro", PROTEIN SCI, 10(9), 2001, pp. 1775-1784

Abstract

The aggregation of beta (2)-microglobulin (beta (2)m) into amyloid fibrils. occurs in the condition known as dialysis-related amyloidosis. (DRA). Theprotein has a beta -sandwich fold typical of the immunoglobulin family, which is stabilized by a highly conserved disulphide bond linking Cys25 and Cys80. Oxidized beta (2)m forms amyloid fibrils rapidly in vitro at acidic pH and high ionic strength. Here we investigate the role of the single disulphide bond of beta (2)m in amyloidosis in vitro. We show that reduction of the disulphide bond destabilizes the native protein such that non-native molecules are populated at neutral pH. These species are prone to oligomerization but do not form amyloid fibrils when incubated for up to 8 mo at pH 7.0 in 0.4 M NaCl. Over the pH range 4.0-1.5 in the presence of 0.4 M NaCl, however, amyloid fibrils of reduced beta (2)m are formed. These fibrils are similar to 10 nm wide, but are shorter and assemble more rapidly than thoseproduced from the oxidized protein. These data show that population of non-native conformers of beta (2)m at neutral pH by reduction of its single disulphide bond is not sufficient for amyloid formation. Instead, associationof one or more specific partially unfolded molecules formed at acid pH arenecessary for the formation of beta (2)m amyloid in vitro. Further experiments will now be needed to determine the role of different oligomeric Species of beta (2)m in the toxicity of the protein in vivo.

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Documento generato il 02/04/20 alle ore 13:06:57