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Biophys. J. BioFAST: First Published September 16, 2005. doi:10.1529/biophysj.105.067538
© 2005 by the Biophysical Society.

A more recent version of this article appeared on December 1, 2005.
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SUPRAMOLECULAR ASSEMBLIES

Amyloid formation of a protein in the absence of unfolding and destabilisation of the native state

Gemma Soldi 1, Francesco Bemporad 1, Silvia Torrassa 2, Annalisa Relini 2, Matteo Ramazzotti 1, Niccolò Taddei 1 and Fabrizio Chiti 1*

1 Università di Firenze
2 Università di Genova

* To whom correspondence should be addressed. E-mail: fchiti{at}scibio.unifi.it.

Submitted on June 13, 2005
Revised on July 29, 2005
Accepted on 6 September 2005


  Abstract
In 5% (v/v) trifluoroethanol, pH 5.5, 25°C one of the acylphosphatases from D. melanogaster (AcPDro2) forms fibrillar aggregates that bind thioflavin T and Congo red and have an extensive {beta}-sheet structure, as revealed by circular dichroism (CD). Atomic force microscopy indicates that the fibrils and their constituent protofilaments have diameters compatible with those of natural amyloid fibrils. Spectroscopic and biochemical investigation, carried out using near- and far-UV CD, intrinsic and ANS-derived fluorescence, dynamic light scattering and enzymatic activity assays, shows that AcPDro2 has, prior to aggregation, a secondary structure content, packing around aromatic and hydrophobic residues, hydrodynamic diameter and catalytic activity indistinguishable from those of the native protein. The native protein was found to have the same conformational stability under native and aggregating conditions, as determined from urea-induced unfolding. The kinetic analysis supports models in which AcPDro2 aggregates initially without need to unfold and subsequently undergoes a conformational change into amyloid-like structures. Although fully or partially unfolded states have a higher propensity to aggregate, the residual aggregation potential that proteins maintain upon complete folding can be physiologically relevant and be directly involved in the pathogenesis of some protein deposition diseases.

Key Words: acylphosphatase, aggregation mechanism, aggregation pathway, misfolding, protein aggregation




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[Abstract] [Full Text] [PDF]


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Copyright © 2005 by the Biophysical Society.