Mechanical forces control the valency of the malaria adhesin VAR2CSA by exposing cryptic glycan binding sites [data] (doi:10.11588/data/EZHMDU)

View:

Part 1: Document Description
Part 2: Study Description
Part 5: Other Study-Related Materials
Entire Codebook

Mechanical forces control the valency of the malaria adhesin VAR2CSA by exposing cryptic glycan binding sites [data]

doi:10.11588/data/EZHMDU

heiDATA

2023-12-04

1

Roessner Rita; Michelarakis, Nicholas; Gräter, Frauke; Aponte-Santamaría, Camilo, 2023, "Mechanical forces control the valency of the malaria adhesin VAR2CSA by exposing cryptic glycan binding sites [data]", https://doi.org/10.11588/data/EZHMDU, heiDATA, V1

Mechanical forces control the valency of the malaria adhesin VAR2CSA by exposing cryptic glycan binding sites [data]

doi:10.11588/data/EZHMDU

Roessner Rita (Molecular Biomechanics Group, Heidelberg Institute for Theoretical Studies, Heidelberg, Germany)

Michelarakis, Nicholas (Molecular Biomechanics Group, Heidelberg Institute for Theoretical Studies, Heidelberg, Germany)

Gräter, Frauke (Molecular Biomechanics Group, Heidelberg Institute for Theoretical Studies, Heidelberg, Germany)

Aponte-Santamaría, Camilo (Molecular Biomechanics Group, Heidelberg Institute for Theoretical Studies, Heidelberg, Germany)

heiDATA

Aponte-Santamaría, Camilo

https://doi.org/10.11588/data/EZHMDU

Medicine, Health and Life Sciences, Physics

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.

Mechanical forces control the valency of the malaria adhesin VAR2CSA by exposing cryptic glycan binding sites. BioRxiv. doi: https://doi.org/10.1101/2023.07.31.550984

Mechanical forces control the valency of the malaria adhesin VAR2CSA by exposing cryptic glycan binding sites. BioRxiv. doi: https://doi.org/10.1101/2023.07.31.550984

Label:

README

Text:

Main README

text/plain; charset=UTF-8

Label:

README-I

text/plain; charset=US-ASCII

Label:

README-II

text/plain; charset=US-ASCII

Label:

README-III

text/plain; charset=US-ASCII

Label:

var2csa_roessner.tar.gz

Text:

Compressed file with all relevant input and output simulation files, as well as code to setup the simulations and analyze the results.

application/gzip