Amorphous Aggregation of Cytochrome c with Inherently Low Amyloidogenicity Is Characterized by the Metastability of Supersaturation and the Phase Diagram

Yuxi Lin, J. Kardos, Mizue Imai, Tatsuya Ikenoue, Misaki Kinoshita, Toshihiko Sugiki, Koichiro Ishimori, Yuji Goto, Young Ho Lee

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Despite extensive studies on the folding and function of cytochrome c, the mechanisms underlying its aggregation remain largely unknown. We herein examined the aggregation behavior of the physiologically relevant two types of cytochrome c, metal-bound cytochrome c, and its fragment with high amyloidogenicity as predicted in alcohol/water mixtures. Although the aggregation propensity of holo cytochrome c was low due to high solubility, markedly unfolded apo cytochrome c, lacking the heme prosthetic group, strongly promoted the propensity for amorphous aggregation with increases in hydrophobicity. Silver-bound apo cytochrome c increased the capacity of fibrillar aggregation (i.e., protofibrils or immature fibrils) due to subtle structural changes of apo cytochrome c by strong binding of silver. However, mature amyloid fibrils were not detected for any of the cytochrome c variants or its fragment, even with extensive ultrasonication, which is a powerful amyloid inducer. These results revealed the intrinsically low amyloidogenicity of cytochrome c, which is beneficial for its homeostasis and function by facilitating the folding and minimizing irreversible amyloid formation. We propose that intrinsically low amyloidogenicity of cytochrome c is attributed to the low metastability of supersaturation. The phase diagram constructed based on solubility and aggregate type is useful for a comprehensive understanding of protein aggregation. Furthermore, amorphous aggregation, which is also viewed as a generic property of proteins, and amyloid fibrillation can be distinguished from each other by the metastability of supersaturation. (Figure Presented).

Original languageEnglish
Pages (from-to)2010-2022
Number of pages13
JournalLangmuir
Volume32
Issue number8
DOIs
Publication statusPublished - Mar 1 2016

Fingerprint

Supersaturation
cytochromes
supersaturation
Cytochromes c
metastable state
Phase diagrams
Agglomeration
phase diagrams
Proteins
Amyloid
Silver
folding
Solubility
Cytochrome c Group
solubility
silver
Amyloidogenic Proteins
fragments
fibrillation
proteins

ASJC Scopus subject areas

  • Electrochemistry
  • Condensed Matter Physics
  • Surfaces and Interfaces
  • Materials Science(all)
  • Spectroscopy

Cite this

Amorphous Aggregation of Cytochrome c with Inherently Low Amyloidogenicity Is Characterized by the Metastability of Supersaturation and the Phase Diagram. / Lin, Yuxi; Kardos, J.; Imai, Mizue; Ikenoue, Tatsuya; Kinoshita, Misaki; Sugiki, Toshihiko; Ishimori, Koichiro; Goto, Yuji; Lee, Young Ho.

In: Langmuir, Vol. 32, No. 8, 01.03.2016, p. 2010-2022.

Research output: Contribution to journalArticle

Lin, Yuxi ; Kardos, J. ; Imai, Mizue ; Ikenoue, Tatsuya ; Kinoshita, Misaki ; Sugiki, Toshihiko ; Ishimori, Koichiro ; Goto, Yuji ; Lee, Young Ho. / Amorphous Aggregation of Cytochrome c with Inherently Low Amyloidogenicity Is Characterized by the Metastability of Supersaturation and the Phase Diagram. In: Langmuir. 2016 ; Vol. 32, No. 8. pp. 2010-2022.
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