[en] The propensity of protein molecules to self-assemble into highly ordered, fibrillar aggregates lies at the heart of understanding many disorders ranging from Alzheimer's disease to systemic lysozyme amyloidosis. In this paper we use highly accurate kinetic measurements of amyloid fibril growth in combination with spectroscopic tools to quantify the effect of modifications in solution conditions and in the amino acid sequence of human lysozyme on its propensity to form amyloid fibrils under acidic conditions. We elucidate and quantify the correlation between the rate of amyloid growth and the population of nonnative states, and we show that changes in amyloidogenicity are almost entirely due to alterations in the stability of the native state, while other regions of the global free-energy surface remain largely unmodified. These results provide insight into the complex dynamics of a macromolecule on a multidimensional energy landscape and point the way for a better understanding of amyloid diseases.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Buell, Alexander K.; University of Cambridge > Nanoscience Centre
Dhulesia, Anne; University of Cambridge > Department of Chemistry
Mossuto, Maria F.
Cremades, Nunilo
Kumita, Janet R.
Dumoulin, Mireille ; Université de Liège - ULiège > Centre d'ingénierie des protéines
Welland, Mark E.
Knowles, Tuomas P. J.
Salvatella, Xavier
Dobson, Christopher M.
Language :
English
Title :
Population of nonnative States of lysozyme variants drives amyloid fibril formation.
Publication date :
2011
Journal title :
Journal of the American Chemical Society
ISSN :
0002-7863
eISSN :
1520-5126
Publisher :
American Chemical Society, Washington, United States - District of Columbia
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