Observation of the Early Structural Changes Leading to the Formation of Protein Superstructures.
Formation of superstructures in protein aggregation processes has been indicated as a general pathway for several proteins, possibly playing a role in human pathologies. There is a severe lack of knowledge on the origin of such species in terms of both mechanisms of formation and structural features. We use equine lysozyme as a model protein, and by combining spectroscopic techniques and microscopy with X-ray fiber diffraction and ab initio modeling of Small Angle X-ray Scattering data, we isolate the partially unfolded state from which one of these superstructures (i.e., particulate) originates. We reveal the low-resolution structure of the unfolded state and its mechanism of formation, highlighting the physicochemical features and the possible pathway of formation of the particulate structure. Our findings provide a novel detailed knowledge of such a general and alternative aggregation pathway for proteins, this being crucial for a basic and broader understanding of the aggregation phenomena.
‡Sector of Biological and Soft Systems, Department of Physics, Cavendish Laboratory, University of Cambridge, 19 J J Thomson Avenue, Cambridge CB3 0HE, United Kingdom.
Vito
V
Foderà
§Dipartimento di Fisica e Chimica, Universitá di Palermo, Viale delle Scienze, Edificio 18, 90128 Palermo, Italy.
Valeria
V
Vetri
Thea S
TS
Wind
∥IRF Life Sciences, KuLeuven KULAK, Etienne Sabbelaan 53, 8500 Kortrijk, Belgium.
Wim
W
Noppe
Claus
C
Cornett
‡Sector of Biological and Soft Systems, Department of Physics, Cavendish Laboratory, University of Cambridge, 19 J J Thomson Avenue, Cambridge CB3 0HE, United Kingdom.
Athene M
AM
Donald
#Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87 Umeå, Sweden.
Ludmilla A
LA
Morozova-Roche
Bente
B
Vestergaard
conformational changes; hydrophobicity; particulate; protein superstructures; unfolded state