Evolution of cation binding in the active sites of P-loop nucleoside triphosphatases in relation to the basic catalytic mechanism

  1. Daria N Shalaeva
  2. Dmitry A Cherepanov
  3. Michael Y Galperin
  4. Andrey V Golovin
  5. Armen Y Mulkidjanian  Is a corresponding author
  1. University of Osnabrück, Germany
  2. Lomonosov Moscow State University, Russian Federation
  3. National Institutes of Health, United States

Abstract

The ubiquitous P-loop fold nucleoside triphosphatases (NTPases) are typically activated by an arginine or lysine 'finger'. Some of the apparently ancestral NTPases are, instead, activated by potassium ions. To clarify the activation mechanism, we combined comparative structure analysis with molecular dynamics (MD) simulations of Mg-ATP and Mg-GTP complexes in water and in the presence of potassium, sodium, or ammonium ions. In all analyzed structures of diverse P-loop NTPases, the conserved P-loop motif keeps the triphosphate chain of bound NTPs (or their analogs) in an extended, catalytically prone conformation, similar to that imposed on NTPs in water by potassium or ammonium ions. MD simulations of potassium-dependent GTPase MnmE showed that linking of alpha- and gamma phosphates by the activating potassium ion led to the rotation of the gamma-phosphate group yielding an almost eclipsed, catalytically productive conformation of the triphosphate chain, which could represent the basic mechanism of hydrolysis by P-loop NTPases.

Data availability

As obtained from MD simulations, we provide the structures of Mg-ATP complexes with bound K+, Na+ or NH4+ ions, as well as the structures of the G-domains of MnmE GTPases with and w/o activating potassium ions as source data files. Simulation data sets have been uploaded to Zenodo (https://zenodo.org/record/1888492#.XAasVhP7RTY).

The following data sets were generated

Article and author information

Author details

  1. Daria N Shalaeva

    School of Physics, University of Osnabrück, Osnabrück, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Dmitry A Cherepanov

    A N Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  3. Michael Y Galperin

    National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2265-5572
  4. Andrey V Golovin

    School of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  5. Armen Y Mulkidjanian

    School of Physics, University of Osnabrück, Osnabrück, Germany
    For correspondence
    amulkid@uos.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5844-3064

Funding

Deutsche Forschungsgemeinschaft (N/A)

  • Armen Y Mulkidjanian

Bundesministerium für Bildung und Forschung (Laseromix)

  • Armen Y Mulkidjanian

Deutscher Akademischer Austauschdienst (Ostpartnerschaftenprogramm)

  • Daria N Shalaeva

Russian Science Foundation (14-50-00029)

  • Daria N Shalaeva
  • Dmitry A Cherepanov

U.S. National Library of Medicine (Intramural Research Program)

  • Michael Y Galperin

Lomonosov Moscow State University (RFMEFI62117X0011)

  • Andrey V Golovin

Osnabrueck University, Germany (EvoCell Program)

  • Armen Y Mulkidjanian

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Nick V Grishin, University of Texas Southwestern Medical Center, United States

Version history

  1. Received: April 9, 2018
  2. Accepted: November 26, 2018
  3. Accepted Manuscript published: December 11, 2018 (version 1)
  4. Version of Record published: December 28, 2018 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Metrics

  • 2,560
    Page views
  • 313
    Downloads
  • 28
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Daria N Shalaeva
  2. Dmitry A Cherepanov
  3. Michael Y Galperin
  4. Andrey V Golovin
  5. Armen Y Mulkidjanian
(2018)
Evolution of cation binding in the active sites of P-loop nucleoside triphosphatases in relation to the basic catalytic mechanism
eLife 7:e37373.
https://doi.org/10.7554/eLife.37373

Share this article

https://doi.org/10.7554/eLife.37373

Further reading

    1. Cell Biology
    2. Evolutionary Biology
    Jonathan E Phillips, Duojia Pan
    Research Advance

    The genomes of close unicellular relatives of animals encode orthologs of many genes that regulate animal development. However, little is known about the function of such genes in unicellular organisms or the evolutionary process by which these genes came to function in multicellular development. The Hippo pathway, which regulates cell proliferation and tissue size in animals, is present in some of the closest unicellular relatives of animals, including the amoeboid organism Capsaspora owczarzaki. We previously showed that the Capsaspora ortholog of the Hippo pathway nuclear effector Yorkie/YAP/TAZ (coYki) regulates actin dynamics and the three-dimensional morphology of Capsaspora cell aggregates, but is dispensable for cell proliferation control (Phillips et al., 2022). However, the function of upstream Hippo pathway components, and whether and how they regulate coYki in Capsaspora, remained unknown. Here, we analyze the function of the upstream Hippo pathway kinases coHpo and coWts in Capsaspora by generating mutant lines for each gene. Loss of either kinase results in increased nuclear localization of coYki, indicating an ancient, premetazoan origin of this Hippo pathway regulatory mechanism. Strikingly, we find that loss of either kinase causes a contractile cell behavior and increased density of cell packing within Capsaspora aggregates. We further show that this increased cell density is not due to differences in proliferation, but rather actomyosin-dependent changes in the multicellular architecture of aggregates. Given its well-established role in cell density-regulated proliferation in animals, the increased density of cell packing in coHpo and coWts mutants suggests a shared and possibly ancient and conserved function of the Hippo pathway in cell density control. Together, these results implicate cytoskeletal regulation but not proliferation as an ancestral function of the Hippo pathway kinase cascade and uncover a novel role for Hippo signaling in regulating cell density in a proliferation-independent manner.

    1. Evolutionary Biology
    2. Immunology and Inflammation
    Zachary Paul Billman, Stephen Bela Kovacs ... Edward A Miao
    Research Article

    Gasdermins oligomerize to form pores in the cell membrane, causing regulated lytic cell death called pyroptosis. Mammals encode five gasdermins that can trigger pyroptosis: GSDMA, B, C, D, and E. Caspase and granzyme proteases cleave the linker regions of and activate GSDMB, C, D, and E, but no endogenous activation pathways are yet known for GSDMA. Here, we perform a comprehensive evolutionary analysis of the gasdermin family. A gene duplication of GSDMA in the common ancestor of caecilian amphibians, reptiles, and birds gave rise to GSDMA–D in mammals. Uniquely in our tree, amphibian, reptile, and bird GSDMA group in a separate clade than mammal GSDMA. Remarkably, GSDMA in numerous bird species contain caspase-1 cleavage sites like YVAD or FASD in the linker. We show that GSDMA from birds, amphibians, and reptiles are all cleaved by caspase-1. Thus, GSDMA was originally cleaved by the host-encoded protease caspase-1. In mammals the caspase-1 cleavage site in GSDMA is disrupted; instead, a new protein, GSDMD, is the target of caspase-1. Mammal caspase-1 uses exosite interactions with the GSDMD C-terminal domain to confer the specificity of this interaction, whereas we show that bird caspase-1 uses a stereotypical tetrapeptide sequence to confer specificity for bird GSDMA. Our results reveal an evolutionarily stable association between caspase-1 and the gasdermin family, albeit a shifting one. Caspase-1 repeatedly changes its target gasdermin over evolutionary time at speciation junctures, initially cleaving GSDME in fish, then GSDMA in amphibians/reptiles/birds, and finally GSDMD in mammals.