Structural basis for inhibition of erythrocyte invasion by antibodies to Plasmodium falciparum protein CyRPA

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Abstract

Plasmodium falciparum causes malaria in humans with over 450,000 deaths annually. The asexual blood stage involves invasion of erythrocytes by merozoites, in which they grow and divide to release daughter merozoites, which in turn invade new erythrocytes perpetuating the cycle responsible for malaria. A key step in merozoite invasion is the essential binding of PfRh5/CyRPA/PfRipr complex to basigin, a step linked to formation of a pore between merozoites and erythrocytes. We show CyRPA interacts directly with PfRh5. An invasion inhibitory monoclonal antibody to CyRPA blocks binding of CyRPA to PfRh5 and complex formation thus illuminating the molecular mechanism for inhibition of parasite growth. We determined the crystal structures of CyRPA alone and in complex with antibody Fab fragment. CyRPA has a six-bladed β-propeller fold, and we identify the region that interacts with PfRh5. This functionally conserved epitope is a potential target for vaccines against P. falciparum.

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Lin Chen

The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

Competing interests
The authors declare that no competing interests exist.
Yibin Xu

The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

Competing interests
The authors declare that no competing interests exist.
Wilson Wong

The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

Competing interests
The authors declare that no competing interests exist.
Jennifer K Thompson

The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

Competing interests
The authors declare that no competing interests exist.
Julie Healer

The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

Competing interests
The authors declare that no competing interests exist.
Ethan Goddard-Borger

The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

Competing interests
The authors declare that no competing interests exist.
Michael C Lawrence

The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

Competing interests
The authors declare that no competing interests exist.
Alan F Cowman

The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

For correspondence
cowman@wehi.edu.au

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-5145-9004

Funding

Victorian State Government OIS and NHMRC IRIISS

Lin Chen
Yibin Xu
Wilson Wong
Jennifer K Thompson
Ethan Goddard-Borger
Michael C Lawrence
Alan F Cowman

Howard Hughes Medical Institute (55007645)

Alan F Cowman

National Health and Medical Research Council (637406)

Alan F Cowman

Path/Malaria Vaccine Initiative (07608-COL)

Alan F Cowman

United States Agency for International Development (07608-COL)

Alan F Cowman

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

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