The crystal structure of yeast mitochondrial type pyrophosphatase provides a model to study pathological mutations in its human ortholog.

Autor: Bezpalaya EY; Lomonosov Moscow State University, Chemistry Department, 119991, Moscow, Russia., Matyuta IO; A.N. Bach Institute of Biochemistry, Federal Research Centre of Biotechnology of the Russian Academy of Sciences, 119071, Moscow, Russia; Landau Phystech School of Physics and Research, Moscow Institute of Physics and Technology, Institutsky Lane, 9, Dolgoprudny, 141700, Moscow, Russia., Vorobyeva NN; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119899, Moscow, Russia., Kurilova SA; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119899, Moscow, Russia., Oreshkov SD; Lomonosov Moscow State University, Chemistry Department, 119991, Moscow, Russia., Minyaev ME; N.D. Zelinsky Institute of Organic Chemistry Russian Academy of Sciences, 119071, Moscow, Russia., Boyko KM; A.N. Bach Institute of Biochemistry, Federal Research Centre of Biotechnology of the Russian Academy of Sciences, 119071, Moscow, Russia. Electronic address: kmb@inbi.ras.ru., Rodina EV; Lomonosov Moscow State University, Chemistry Department, 119991, Moscow, Russia. Electronic address: rodina@belozersky.msu.ru.
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2024 Dec 17; Vol. 738, pp. 150563. Date of Electronic Publication: 2024 Aug 17.
DOI: 10.1016/j.bbrc.2024.150563
Abstrakt: Mutations in human ppa2 gene encoding mitochondrial inorganic pyrophosphatase (PPA2) result in the mitochondria malfunction in heart and brain and lead to early death. In comparison with its cytosolic counterpart, PPA2 of any species is a poorly characterized enzyme with a previously unknown 3D structure. We report here the crystal structure of PPA2 from yeast Ogataea parapolymorpha (OpPPA2), as well as its biochemical characterization. OpPPA2 is a dimer, demonstrating the fold typical for other eukaryotic Family I pyrophosphatases, including the human cytosolic enzyme. Cofactor Mg 2+ ions found in OpPPA2 structure have similar coordination to most known Family I pyrophosphatases. Most of the residues associated with the pathological mutations in human PPA2 are conserved in OpPPA2, and their structural context suggests possible explanations for the effects of the mutations on the human enzyme. In this work, the mutant variant of OpPPA2, Met52Val, corresponding to the natural pathogenic variant Met94Val of human PPA2, is characterized. The obtained structural and biochemical data provide a step to understanding the structural basis of PPA2-associated pathologies.
Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest.
(Copyright © 2024. Published by Elsevier Inc.)
Databáze: MEDLINE
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