An evolutionarily conserved mechanism controls reversible amyloids of pyruvate kinase via pH-sensing regions.
Dev Cell
; 59(14): 1876-1891.e7, 2024 Jul 22.
Article
em En
| MEDLINE
| ID: mdl-38788715
ABSTRACT
Amyloids are known as irreversible aggregates associated with neurodegenerative diseases. However, recent evidence shows that a subset of amyloids can form reversibly and fulfill essential cellular functions. Yet, the molecular mechanisms regulating functional amyloids and distinguishing them from pathological aggregates remain unclear. Here, we investigate the conserved principles of amyloid reversibility by studying the essential metabolic enzyme pyruvate kinase (PK) in yeast and human cells. We demonstrate that yeast PK (Cdc19) and human PK (PKM2) form reversible amyloids through a pH-sensitive amyloid core. Stress-induced cytosolic acidification promotes aggregation via protonation of specific glutamate (yeast) or histidine (human) residues within the amyloid core. Mutations mimicking protonation cause constitutive PK aggregation, while non-protonatable PK mutants remain soluble even upon stress. Physiological PK aggregation is coupled to metabolic rewiring and glycolysis arrest, causing severe growth defects when misregulated. Our work thus identifies an evolutionarily conserved, potentially widespread mechanism regulating functional amyloids during stress.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piruvato Quinase
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Saccharomyces cerevisiae
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Proteínas de Saccharomyces cerevisiae
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Amiloide
Limite:
Humans
Idioma:
En
Revista:
Dev Cell
Ano de publicação:
2024
Tipo de documento:
Article