Malaria parasites use a soluble RhopH complex for erythrocyte invasion and an integral form for nutrient uptake
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States
- National Cancer Institute, NIH, United States
- Johns Hopkins Bloomberg School of Public Health, United States
- The Rockefeller University, United States
- University of British Columbia, Canada
Abstract
Malaria parasites use the RhopH complex for erythrocyte invasion and channel-mediated nutrient uptake. As the member proteins are unique to Plasmodium spp., how they interact and traffic through subcellular sites to serve these essential functions is unknown. We show that RhopH is synthesized as a soluble complex of CLAG3, RhopH2, and RhopH3 with 1:1:1 stoichiometry. After transfer to a new host cell, the complex crosses a vacuolar membrane surrounding the intracellular parasite and becomes integral to the erythrocyte membrane through a PTEX translocon-dependent process. We present a 2.9 Å single-particle cryo-electron microscopy structure of the trafficking complex, revealing that CLAG3 interacts with the other subunits over large surface areas. This soluble complex is tightly assembled with extensive disulfide bonding and predicted transmembrane helices shielded. We propose a large protein complex stabilized for trafficking but poised for host membrane insertion through large-scale rearrangements, paralleling smaller two-state pore-forming proteins in other organisms.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Cryo-EM maps have been deposited in EMDB and PDB.
Article and author information
Author details
Sriram Subramaniam
Funding
National Institute of Allergy and Infectious Diseases
- Sanjay A Desai
National Cancer Institute
- Sriram Subramaniam
National Institutes of Health (P41 GM103314)
- Brian T Chait
National Institutes of Health (P41 GM109824)
- Michael P Rout
- Brian T Chait
Canada Excellence Research Chairs, Government of Canada
- Sriram Subramaniam
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Olivier Silvie, Sorbonne Université, UPMC Univ Paris 06, INSERM, CNRS, France
Version history
- Received: November 29, 2020
- Accepted: January 4, 2021
- Accepted Manuscript published: January 4, 2021 (version 1)
- Accepted Manuscript updated: January 5, 2021 (version 2)
- Version of Record published: January 27, 2021 (version 3)
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.
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Malaria parasites use a soluble RhopH complex for erythrocyte invasion and an integral form for nutrient uptake
eLife 10:e65282.
https://doi.org/10.7554/eLife.65282
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