title: Population of nonnative states of lysozyme variants drives amyloid fibril formation.
abstract: 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.
authors.affiliation: Nanoscience Centre, University of Cambridge, 11 JJ Thomson Avenue, Cambridge CB3 0FF, UK.
authors.forename: Alexander K
authors.initials: AK
authors.lastname: Buell
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Dhulesia
authors.affiliation: Institute for Research in Biomedicine (IRB), Baldiri Reixac 10, 08028 Barcelona, Spain.
authors.forename: Maria F
authors.initials: MF
authors.lastname: Mossuto
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Nunilo
authors.initials: N
authors.lastname: Cremades
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Janet R
authors.initials: JR
authors.lastname: Kumita
authors.affiliation: Centre for Protein Engineering, University of Liège, Sart Tilman, 4000 Liège, Belgium.
authors.forename: Mireille
authors.initials: M
authors.lastname: Dumoulin
authors.affiliation: Nanoscience Centre, University of Cambridge, 11 JJ Thomson Avenue, Cambridge CB3 0FF, UK.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Welland
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Tuomas P J
authors.initials: TPJ
authors.lastname: Knowles
authors.affiliation: Institute for Research in Biomedicine (IRB), Baldiri Reixac 10, 08028 Barcelona, Spain.|Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluis Companys 23, 08010 Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Salvatella
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
mesh_terms: D000682:Amyloid / Q000096:biosynthesis*; D006801:Humans; D009113:Muramidase / Q000737:chemistry*
chemical_list: D000682:Amyloid; D009113:Muramidase