A Population Shift between Sparsely Populated Folding Intermediates Determines Amyloidogenicity.
The balance between protein folding and misfolding is a crucial determinant of amyloid assembly. Transient intermediates that are sparsely populated during protein folding have been identified as key players in amyloid aggregation. However, due to their ephemeral nature, structural characterization of these species remains challenging. Here, using the power of nonuniformly sampled NMR methods we investigate the folding pathway of amyloidogenic and nonamyloidogenic variants of β2-microglobulin (β2m) in atomic detail. Despite folding via common intermediate states, we show that the decreased population of the aggregation-prone ITrans state and population of a less stable, more dynamic species ablate amyloid formation by increasing the energy barrier for amyloid assembly. The results show that subtle changes in conformational dynamics can have a dramatic effect in determining whether a protein is amyloidogenic, without perturbation of the mechanism of protein folding.
Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, University of Leeds , Leeds LS2 9JT, U.K.
Theodoros K
TK
Karamanos
Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, University of Leeds , Leeds LS2 9JT, U.K.
Clare L
CL
Pashley
Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, University of Leeds , Leeds LS2 9JT, U.K.
Arnout P
AP
Kalverda
Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, University of Leeds , Leeds LS2 9JT, U.K.
Gary S
GS
Thompson
The Swedish NMR Centre, University of Gothenburg , Box 465, 40530 Göteborg, Sweden.
Maxim
M
Mayzel
The Swedish NMR Centre, University of Gothenburg , Box 465, 40530 Göteborg, Sweden.|Department of Chemistry and Molecular Biology, University of Gothenburg , Box 465, 40530 Göteborg, Sweden.
Vladislav Y
VY
Orekhov
Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, University of Leeds , Leeds LS2 9JT, U.K.
Sheena E
SE
Radford
D000682:Amyloid / Q000737:chemistry*; D058227:Amyloidogenic Proteins / Q000737:chemistry*; D004926:Escherichia coli / Q000737:chemistry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010957:Plasmids / Q000737:chemistry; D011487:Protein Conformation; D017510:Protein Folding; D013816:Thermodynamics; D001613:beta 2-Microglobulin / Q000737:chemistry
D000682:Amyloid; D058227:Amyloidogenic Proteins; D001613:beta 2-Microglobulin