Sucrose prevents protein fibrillation through compaction of the tertiary structure but hardly affects the secondary structure

• Published in: Proteins, structure, function, and bioinformatics structure, function, and bioinformatics, 2015-11, Vol.83 (11), p.2039-2051
• Main Authors: Estrela, Nídia, Franquelim, Henri G., Lopes, Carlos, Tavares, Evandro, Macedo, Joana A., Christiansen, Gunna, Otzen, Daniel E., Melo, Eduardo P.
• Format: Article
• Language: English
• Subjects: Amyloid - chemistry; Amyloid - metabolism; osmolytes; Protein Aggregates - drug effects; Protein Conformation; Protein Engineering; protein fibrillation; S6 protein; Sucrose - chemistry; Sucrose - pharmacology
• ISSN: 0887-3585; 1097-0134
• DOI: 10.1002/prot.24921

ABSTRACT Amyloid fibers, implicated in a wide range of diseases, are formed when proteins misfold and stick together in long rope‐like structures. As a natural mechanism, osmolytes can be used to modulate protein aggregation pathways with no interference with other cellular functions. The osmolyte sucrose delays fibrillation of the ribosomal protein S6 leading to softer and less shaped‐defined fibrils. The molecular mechanism used by sucrose to delay S6 fibrillation was studied based on the two‐state unfolding kinetics of the secondary and tertiary structures. It was concluded that the delay in S6 fibrillation results from stabilization and compaction of the slightly expanded tertiary native structure formed under fibrillation conditions. Interestingly, this compaction extends to almost all S6 tertiary structure but hardly affects its secondary structure. The part of the S6 tertiary structure that suffered more compaction by sucrose is known to be the first part to unfold, indicating that the native S6 has entered the unfolding pathway under fibrillation conditions. Proteins 2015; 83:2039–2051. © 2015 Wiley Periodicals, Inc.