Journal
COMMUNICATIONS BIOLOGY
Volume 4, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s42003-020-01641-6
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Funding
- Cooperative Research Program for the Institute for Protein Research, Osaka University [CR-19-02]
- Ministry of Education, Culture, Sports, Science and Technology [17H06352]
- Japan Society for the Promotion of Science [20K06580]
- SENTAN from the Japan Agency for Medical Research and Development, AMED
- National Research, Development and Innovation Fund of Hungary [K120391, 2017-1.2.1-NKP-2017-00002, 2019-2.1.11-TET2019-00079]
- Lundbeck Foundation [R276-2018-671]
- Novo Nordisk Foundation [NNF17OC0028806]
- Danish Research Council \ Technology and Production [6111-00241B]
- Grants-in-Aid for Scientific Research [17H06352, 20K06580] Funding Source: KAKEN
- MRC [MR/K000187/1] Funding Source: UKRI
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Noji et al. test the link between protein folding and misfolding upon heating and agitation, showing 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 valuable for understanding protein folding versus self-assembly and amyloidogenesis.
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.
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