Observation of the Early Structural Changes Leading to the Formation of Protein Superstructures

• Published in: The journal of physical chemistry letters 2014-09, Vol.5 (18), p.3254-3258
• Main Authors: Foderà, Vito, Vetri, Valeria, Wind, Thea S, Noppe, Wim, Cornett, Claus, Donald, Athene M, Morozova-Roche, Ludmilla A, Vestergaard, Bente
• Format: Article
• Language: English
• Subjects: Biophysical Chemistry and Biomolecules
• ISSN: 1948-7185; 1948-7185
• DOI: 10.1021/jz501614e

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.