Mechanical forces control the valency of the malaria adhesin VAR2CSA by exposing cryptic glycan binding sites.

Autor: Roessner R; Molecular Biomechanics Group, Heidelberg Institute for Theoretical Studies, Heidelberg, Germany., Michelarakis N; Molecular Biomechanics Group, Heidelberg Institute for Theoretical Studies, Heidelberg, Germany., Gräter F; Molecular Biomechanics Group, Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.; Interdisciplinary Center for Scientific Computing, Heidelberg University, Heidelberg, Germany., Aponte-Santamaría C; Molecular Biomechanics Group, Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.
Jazyk: angličtina
Zdroj: PLoS computational biology [PLoS Comput Biol] 2023 Dec 20; Vol. 19 (12), pp. e1011726. Date of Electronic Publication: 2023 Dec 20 (Print Publication: 2023).
DOI: 10.1371/journal.pcbi.1011726
Abstrakt: Plasmodium falciparum (Pf) is responsible for the most lethal form of malaria. VAR2CSA is an adhesin protein expressed by this parasite at the membrane of infected erythrocytes for attachment to the placenta, leading to pregnancy-associated malaria. VAR2CSA is a large 355 kDa multidomain protein composed of nine extracellular domains, a transmembrane helix, and an intracellular domain. VAR2CSA binds to Chondroitin Sulphate A (CSA) of the proteoglycan matrix of the placenta. Shear flow, as the one occurring in blood, has been shown to enhance the (VAR2CSA-mediated) adhesion of Pf-infected erythrocytes on the CSA-matrix. However, the underlying molecular mechanism governing this enhancement has remained elusive. Here, we address this question by using equilibrium, force-probe, and docking-based molecular dynamics simulations. We subjected the VAR2CSA protein-CSA sugar complex to a force mimicking the tensile force exerted on this system due to the shear of the flowing blood. We show that upon this force exertion, VAR2CSA undergoes a large opening conformational transition before the CSA sugar chain dissociates from its main binding site. This preferential order of events is caused by the orientation of the molecule during elongation, as well as the strong electrostatic attraction of the sugar to the main protein binding site. Upon opening, two additional cryptic CSA binding sites get exposed and a functional dodecameric CSA molecule can be stably accommodated at these force-exposed positions. Thus, our results suggest that mechanical forces increase the avidity of VAR2CSA by turning it from a monovalent to a multivalent state. We propose this to be the molecular cause of the observed shear-enhanced adherence. Mechanical control of the valency of VAR2CSA is an intriguing hypothesis that can be tested experimentally and which is of relevance for the understanding of the malaria infection and for the development of anti placental-malaria vaccines targeting VAR2CSA.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2023 Roessner et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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