An evolutionarily conserved mechanism controls reversible amyloids of pyruvate kinase via pH-sensing regions.

Autor:	Cereghetti G; Institute of Biochemistry, Department of Biology, ETH Zürich, 8093 Zürich, Switzerland; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, CB2 1EW Cambridge, UK. Electronic address: gssc3@cam.ac.uk., Kissling VM; Institute of Biochemistry, Department of Biology, ETH Zürich, 8093 Zürich, Switzerland; Particles-Biology Interactions Laboratory, Department of Materials Meet Life, Empa, 9014 St. Gallen, Switzerland., Koch LM; Institute of Biochemistry, Department of Biology, ETH Zürich, 8093 Zürich, Switzerland., Arm A; Institute of Biochemistry, Department of Biology, ETH Zürich, 8093 Zürich, Switzerland., Schmidt CC; Institute of Biochemistry, Department of Biology, ETH Zürich, 8093 Zürich, Switzerland., Thüringer Y; Institute of Biochemistry, Department of Biology, ETH Zürich, 8093 Zürich, Switzerland., Zamboni N; Institute of Molecular Systems Biology, Department of Biology, ETH Zürich, 8093 Zürich, Switzerland., Afanasyev P; Cryo-EM Knowledge Hub (CEMK), ETH Zurich, 8093 Zürich, Switzerland., Linsenmeier M; Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093 Zürich, Switzerland., Eichmann C; Laboratory of Physical Chemistry, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093 Zürich, Switzerland., Kroschwald S; Institute of Biochemistry, Department of Biology, ETH Zürich, 8093 Zürich, Switzerland., Zhou J; Department of Health Sciences & Technology, ETH Zürich, 8092 Zürich, Switzerland., Cao Y; Department of Health Sciences & Technology, ETH Zürich, 8092 Zürich, Switzerland., Pfizenmaier DM; Institute of Biochemistry, Department of Biology, ETH Zürich, 8093 Zürich, Switzerland., Wiegand T; Laboratory of Physical Chemistry, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093 Zürich, Switzerland; Max Planck Institute for Chemical Energy Conversion, 45470 Mülheim an der Ruhr, Germany; Institute of Technical and Macromolecular Chemistry, RWTH Aachen University, 52074 Aachen, Germany., Cadalbert R; Laboratory of Physical Chemistry, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093 Zürich, Switzerland., Gupta G; Particles-Biology Interactions Laboratory, Department of Materials Meet Life, Empa, 9014 St. Gallen, Switzerland., Boehringer D; Cryo-EM Knowledge Hub (CEMK), ETH Zurich, 8093 Zürich, Switzerland., Knowles TPJ; Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, CB2 1EW Cambridge, UK., Mezzenga R; Department of Health Sciences & Technology, ETH Zürich, 8092 Zürich, Switzerland., Arosio P; Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093 Zürich, Switzerland., Riek R; Laboratory of Physical Chemistry, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093 Zürich, Switzerland., Peter M; Institute of Biochemistry, Department of Biology, ETH Zürich, 8093 Zürich, Switzerland. Electronic address: matthias.peter@bc.biol.ethz.ch.
Jazyk:	angličtina
Zdroj:	Developmental cell [Dev Cell] 2024 Jul 22; Vol. 59 (14), pp. 1876-1891.e7. Date of Electronic Publication: 2024 May 23.
DOI:	10.1016/j.devcel.2024.04.018
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024. Published by Elsevier Inc.)
Databáze:	MEDLINE
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