Breakdown of supersaturation barrier links protein folding to amyloid formation

• Published in: Communications biology Vol. 4; no. 1; p. 120
• Main Authors: Noji, Masahiro, Samejima, Tatsushi, Yamaguchi, Keiichi, So, Masatomo, Yuzu, Keisuke, Chatani, Eri, Akazawa-Ogawa, Yoko, Hagihara, Yoshihisa, Kawata, Yasushi, Ikenaka, Kensuke, Mochizuki, Hideki, Kardos, József, Otzen, Daniel E., Bellotti, Vittorio, Buchner, Johannes, Goto, Yuji
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.01.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 101/47; 631/45/470/2284; 631/57/2269; Agitation; alpha-Synuclein - chemistry; alpha-Synuclein - metabolism; Amino acid sequence; Amino Acid Sequence - physiology; Amyloid - chemistry; Amyloid - metabolism; Amyloidogenesis; Amyloidosis - etiology; Amyloidosis - metabolism; Biology; Biomedical and Life Sciences; Chemical Precipitation; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - metabolism; Fibrils; Free energy; High temperature; Humans; Intrinsically Disordered Proteins - chemistry; Intrinsically Disordered Proteins - metabolism; Islet Amyloid Polypeptide - chemistry; Islet Amyloid Polypeptide - metabolism; Life Sciences; Osmolar Concentration; Protein Aggregation, Pathological - etiology; Protein Aggregation, Pathological - metabolism; Protein Conformation; Protein Folding; Protein Multimerization - physiology; Protein structure; Self-assembly; tau Proteins - chemistry; tau Proteins - metabolism; Thermodynamics
• DOI: 10.1038/s42003-020-01641-6
• ISSN: 2399-3642

The thermodynamic hypothesis of protein folding, known as the “Anfinsen’s dogma” states that the native structure of a protein represents a free energy minimum determined by the amino acid sequence. However, inconsistent with the Anfinsen’s dogma, globular proteins can misfold to form amyloid fibrils, which are ordered aggregates associated with diseases such as Alzheimer’s and Parkinson’s diseases. Here, we present a general concept for the link between folding and misfolding. We tested the accessibility of the amyloid state for various proteins upon heating and agitation. Many of them showed Anfinsen-like reversible unfolding upon heating, but formed amyloid fibrils upon agitation at high temperatures. We show that folding and amyloid formation are separated by the supersaturation barrier of a protein. Its breakdown is required to shift the protein to the amyloid pathway. Thus, the breakdown of supersaturation links the Anfinsen’s intramolecular folding universe and the intermolecular misfolding universe. Noji et al. test link between protein folding and misfolding upon heating and agitation. They show that folding and amyloid formation are separated by the supersaturation barrier of a protein, breakdown of which shifts the protein to the amyloid pathway. This study is useful to the field of protein folding versus self-assembly and amyloidogenesis.