Breakdown of supersaturation barrier links protein folding to amyloid formation

Masahiro Noji; Tatsushi Samejima; Keiichi Yamaguchi; Masatomo So; Keisuke Yuzu; Eri Chatani; Yoko Akazawa-Ogawa; Yoshihisa Hagihara; Yasushi Kawata; Kensuke Ikenaka; Hideki Mochizuki; József Kardos; Daniel E Otzen; Vittorio Bellotti; Johannes Buchner; Yuji Goto

doi:10.1038/s42003-020-01641-6

Breakdown of supersaturation barrier links protein folding to amyloid formation

Masahiro Noji, Tatsushi Samejima, Keiichi Yamaguchi, Masatomo So, Keisuke Yuzu, Eri Chatani, Yoko Akazawa-Ogawa, Yoshihisa Hagihara, Yasushi Kawata, Kensuke Ikenaka, Hideki Mochizuki, József Kardos, Daniel E Otzen, Vittorio Bellotti, Johannes Buchner, Yuji Goto^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

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.

Original language	English
Article number	120
Journal	Communications Biology
Volume	4
Issue	1
Number of pages	10
DOIs	https://doi.org/10.1038/s42003-020-01641-6
Publication status	Published - Jan 2021

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Noji, M., Samejima, T., Yamaguchi, K., So, M., Yuzu, K., Chatani, E., Akazawa-Ogawa, Y., Hagihara, Y., Kawata, Y., Ikenaka, K., Mochizuki, H., Kardos, J., Otzen, D. E., Bellotti, V., Buchner, J., & Goto, Y. (2021). Breakdown of supersaturation barrier links protein folding to amyloid formation. Communications Biology, 4(1), Article 120. https://doi.org/10.1038/s42003-020-01641-6

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title = "Breakdown of supersaturation barrier links protein folding to amyloid formation",

abstract = "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.",

author = "Masahiro Noji and Tatsushi Samejima and Keiichi Yamaguchi and Masatomo So and Keisuke Yuzu and Eri Chatani and Yoko Akazawa-Ogawa and Yoshihisa Hagihara and Yasushi Kawata and Kensuke Ikenaka and Hideki Mochizuki and J{\'o}zsef Kardos and Otzen, {Daniel E} and Vittorio Bellotti and Johannes Buchner and Yuji Goto",

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T1 - Breakdown of supersaturation barrier links protein folding to amyloid formation

AU - Noji, Masahiro

AU - Samejima, Tatsushi

AU - Yamaguchi, Keiichi

AU - So, Masatomo

AU - Yuzu, Keisuke

AU - Chatani, Eri

AU - Akazawa-Ogawa, Yoko

AU - Hagihara, Yoshihisa

AU - Kawata, Yasushi

AU - Ikenaka, Kensuke

AU - Mochizuki, Hideki

AU - Kardos, József

AU - Otzen, Daniel E

AU - Bellotti, Vittorio

AU - Buchner, Johannes

AU - Goto, Yuji

PY - 2021/1

Y1 - 2021/1

N2 - 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.

AB - 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.

U2 - 10.1038/s42003-020-01641-6

DO - 10.1038/s42003-020-01641-6

M3 - Journal article

C2 - 33500517

SN - 2399-3642

VL - 4

JO - Communications Biology

JF - Communications Biology

IS - 1

M1 - 120

ER -

Breakdown of supersaturation barrier links protein folding to amyloid formation

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