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Maturation and substrate processing topography of the Plasmodium falciparum invasion/egress protease plasmepsin X

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  • Sumit Mukherjee

    (Washington University School of Medicine)

  • Suong Nguyen

    (Washington University School of Medicine)

  • Eashan Sharma

    (Washington University School of Medicine)

  • Daniel E. Goldberg

    (Washington University School of Medicine)

Abstract

The malaria parasite Plasmodium invades a host erythrocyte, multiplies within a parasitophorous vacuole (PV) and then ruptures the PV and erythrocyte membranes in a process known as egress. Both egress and invasion are controlled by effector proteins discharged from specialized secretory organelles. The aspartic protease plasmepsin X (PM X) regulates activity for many of these effectors, but it is unclear how PM X accesses its diverse substrates that reside in different organelles. PM X also autoprocesses to generate different isoforms. The function of this processing is not understood. We have mapped the self-cleavage sites and have constructed parasites with cleavage site mutations. Surprisingly, a quadruple mutant that remains full-length retains in vitro activity, is trafficked normally, and supports normal egress, invasion and parasite growth. The N-terminal half of the prodomain stays bound to the catalytic domain even after processing and is required for proper intracellular trafficking of PM X. We find that this enzyme cleaves microneme and exoneme substrates before discharge, while the rhoptry substrates that are dependent on PM X activity are cleaved after exoneme discharge into the PV. The data give insight into the temporal, spatial and biochemical control of this unusual but important aspartic protease.

Suggested Citation

  • Sumit Mukherjee & Suong Nguyen & Eashan Sharma & Daniel E. Goldberg, 2022. "Maturation and substrate processing topography of the Plasmodium falciparum invasion/egress protease plasmepsin X," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32271-7
    DOI: 10.1038/s41467-022-32271-7
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    References listed on IDEAS

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    1. Justin A. Boddey & Anthony N. Hodder & Svenja Günther & Paul R. Gilson & Heather Patsiouras & Eugene A. Kapp & J. Andrew Pearce & Tania F. de Koning-Ward & Richard J. Simpson & Brendan S. Crabb & Alan, 2010. "An aspartyl protease directs malaria effector proteins to the host cell," Nature, Nature, vol. 463(7281), pages 627-631, February.
    2. Eva S. Istvan & Jeremy P. Mallari & Victoria C. Corey & Neekesh V. Dharia & Garland R. Marshall & Elizabeth A. Winzeler & Daniel E. Goldberg, 2017. "Esterase mutation is a mechanism of resistance to antimalarial compounds," Nature Communications, Nature, vol. 8(1), pages 1-8, April.
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    1. Mubasher Mohammed & Alexis Dziedziech & Diego Macedo & Frederik Huppertz & Ylva Veith & Zoé Postel & Elena Christ & Richard Scheytt & Tanja Slotte & Johan Henriksson & Johan Ankarklev, 2024. "Single-cell transcriptomics reveal transcriptional programs underlying male and female cell fate during Plasmodium falciparum gametocytogenesis," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Madeline G. Dans & Coralie Boulet & Gabrielle M. Watson & William Nguyen & Jerzy M. Dziekan & Cindy Evelyn & Kitsanapong Reaksudsan & Somya Mehra & Zahra Razook & Niall D. Geoghegan & Michael J. Mlodz, 2024. "Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. Tony Triglia & Stephen W. Scally & Benjamin A. Seager & Michał Pasternak & Laura F. Dagley & Alan F. Cowman, 2023. "Plasmepsin X activates the PCRCR complex of Plasmodium falciparum by processing PfRh5 for erythrocyte invasion," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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