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Breakdown of supersaturation barrier links protein folding to amyloid formation.

Masahiro NojiTatsushi SamejimaKeiichi YamaguchiMasatomo SoKeisuke YuzuEri ChataniYoko Akazawa-OgawaYoshihisa HagiharaYasushi KawataKensuke IkenakaHideki MochizukiJózsef KardosDaniel Erik OtzenVittorio BellottiJohannes BuchnerYuji Goto
Published in: Communications biology (2021)
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.
Keyphrases
  • amino acid
  • single molecule
  • molecular dynamics simulations
  • protein protein
  • binding protein