The assembly of proteins into highly organized fibrillar aggregates is a key process in biology, biotechnology, and human disease. It has been shown that proteins retain a small, yet significant propensity to aggregate when they are folded into compact globular structures, and this may be physiologically relevant, particularly when considering that proteins spend most of their lifespan into such compact states. Proteins from the acylphosphatase-like structural family have been shown to aggregate via different mechanisms, with some members forming native-like aggregates as a first step of their aggregation process and others requiring unfolding as a first necessary step. Here we use the acylphosphatase from Sulfolobus solfataricus to show that assembly of folded protein molecules into native-like aggregates is prevented by single-point mutations that introduce structural protections within one of the most flexible region of the protein, the peripheral edge beta-strand 4. The resulting mutants do not form native-like aggregates, but can still form thioflavin T-binding and beta-structured oligomers, albeit more slowly than the wild-type protein. The kinetic data show that formation of the latter species proceeds via an alternative mechanism that is independent of the transient formation of native-like aggregates.

The degree of structural protection at the edge beta-strands determines the pathway of amyloid formation in globular proteins / G. SOLDI; F. BEMPORAD; F. CHITI. - In: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY. - ISSN 0002-7863. - STAMPA. - 130:(2008), pp. 4295-4302. [10.1021/ja076628s]

The degree of structural protection at the edge beta-strands determines the pathway of amyloid formation in globular proteins.

BEMPORAD, FRANCESCO;CHITI, FABRIZIO
2008

Abstract

The assembly of proteins into highly organized fibrillar aggregates is a key process in biology, biotechnology, and human disease. It has been shown that proteins retain a small, yet significant propensity to aggregate when they are folded into compact globular structures, and this may be physiologically relevant, particularly when considering that proteins spend most of their lifespan into such compact states. Proteins from the acylphosphatase-like structural family have been shown to aggregate via different mechanisms, with some members forming native-like aggregates as a first step of their aggregation process and others requiring unfolding as a first necessary step. Here we use the acylphosphatase from Sulfolobus solfataricus to show that assembly of folded protein molecules into native-like aggregates is prevented by single-point mutations that introduce structural protections within one of the most flexible region of the protein, the peripheral edge beta-strand 4. The resulting mutants do not form native-like aggregates, but can still form thioflavin T-binding and beta-structured oligomers, albeit more slowly than the wild-type protein. The kinetic data show that formation of the latter species proceeds via an alternative mechanism that is independent of the transient formation of native-like aggregates.
2008
130
4295
4302
G. SOLDI; F. BEMPORAD; F. CHITI
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/315631
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