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

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

Journal

Biochemical and Biophysical Research Communications
ISSN: 0006-291X , E-ISSN: 1090-2104

Output data

Year: 2024, Volume: 738, Article number : 150563, Pages count : DOI: 10.1016/j.bbrc.2024.150563

Authors

Bezpalaya Ekaterina Y ¹ , Matyuta Ilya O ² , Vorobyeva Natalia N ³ , Kurilova Svetlana A ³ , Oreshkov Sergey D ¹ , Minyaev Mikhail E ⁴ , Boyko Konstantin M ² , Rodina Elena V ¹

Affiliations

1	Lomonosov Moscow State University, Chemistry Department, 119991, Moscow, Russia.
2	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.
3	Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119899, Moscow, Russia.
4	N.D. Zelinsky Institute of Organic Chemistry Russian Academy of Sciences, 119071, Moscow, Russia.

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 Mg2+ 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.

Bezpalaya E.Y. , Matyuta I.O. , Vorobyeva N.N. , Kurilova S.A. , Oreshkov S.D. , Minyaev M.E. , Boyko K.M. , Rodina E.V.
The crystal structure of yeast mitochondrial type pyrophosphatase provides a model to study pathological mutations in its human ortholog
Biochemical and Biophysical Research Communications. 2024. V.738. 150563 . DOI: 10.1016/j.bbrc.2024.150563 WOS Scopus OpenAlex

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