Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding

Research output: Contribution to journal › Journal article › Research › peer-review

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Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding. / Wang, Kaituo; Dagil, Robert; Lavstsen, Thomas; Misra, Sandeep K; Spliid, Charlotte B.; Wang, Yong; Gustavsson, Tobias; Sandoval, Daniel R.; Vidal-Calvo, Elena Ethel; Choudhary, Swati; Agerbaek, Mette Ø.; Lindorff-Larsen, Kresten; Nielsen, Morten A.; Theander, Thor G.; Sharp, Joshua S; Clausen, Thomas Mandel; Gourdon, Pontus; Salanti, Ali.

In: Nature Communications, Vol. 12, No. 1, 2956, 2021.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Wang, K, Dagil, R, Lavstsen, T, Misra, SK, Spliid, CB, Wang, Y, Gustavsson, T, Sandoval, DR, Vidal-Calvo, EE, Choudhary, S, Agerbaek, MØ, Lindorff-Larsen, K, Nielsen, MA, Theander, TG, Sharp, JS, Clausen, TM, Gourdon, P & Salanti, A 2021, 'Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding', Nature Communications, vol. 12, no. 1, 2956. https://doi.org/10.1038/s41467-021-23254-1

APA

Wang, K., Dagil, R., Lavstsen, T., Misra, S. K., Spliid, C. B., Wang, Y., Gustavsson, T., Sandoval, D. R., Vidal-Calvo, E. E., Choudhary, S., Agerbaek, M. Ø., Lindorff-Larsen, K., Nielsen, M. A., Theander, T. G., Sharp, J. S., Clausen, T. M., Gourdon, P., & Salanti, A. (2021). Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding. Nature Communications, 12(1), [2956]. https://doi.org/10.1038/s41467-021-23254-1

Vancouver

Wang K, Dagil R, Lavstsen T, Misra SK, Spliid CB, Wang Y et al. Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding. Nature Communications. 2021;12(1). 2956. https://doi.org/10.1038/s41467-021-23254-1

Author

Wang, Kaituo ; Dagil, Robert ; Lavstsen, Thomas ; Misra, Sandeep K ; Spliid, Charlotte B. ; Wang, Yong ; Gustavsson, Tobias ; Sandoval, Daniel R. ; Vidal-Calvo, Elena Ethel ; Choudhary, Swati ; Agerbaek, Mette Ø. ; Lindorff-Larsen, Kresten ; Nielsen, Morten A. ; Theander, Thor G. ; Sharp, Joshua S ; Clausen, Thomas Mandel ; Gourdon, Pontus ; Salanti, Ali. / Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding. In: Nature Communications. 2021 ; Vol. 12, No. 1.

Bibtex

@article{13a100cfc5af453f973dc570e66e05bb,
title = "Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding",
abstract = "Placental malaria can have severe consequences for both mother and child and effective vaccines are lacking. Parasite-infected red blood cells sequester in the placenta through interaction between parasite-expressed protein VAR2CSA and the glycosaminoglycan chondroitin sulfate A (CS) abundantly present in the intervillous space. Here, we report cryo-EM structures of the VAR2CSA ectodomain at up to 3.1 {\AA} resolution revealing an overall V-shaped architecture and a complex domain organization. Notably, the surface displays a single significantly electropositive patch, compatible with binding of negatively charged CS. Using molecular docking and molecular dynamics simulations as well as comparative hydroxyl radical protein foot-printing of VAR2CSA in complex with placental CS, we identify the CS-binding groove, intersecting with the positively charged patch of the central VAR2CSA structure. We identify distinctive conserved structural features upholding the macro-molecular domain complex and CS binding capacity of VAR2CSA as well as divergent elements possibly allowing immune escape at or near the CS binding site. These observations will support rational design of second-generation placental malaria vaccines.",
author = "Kaituo Wang and Robert Dagil and Thomas Lavstsen and Misra, {Sandeep K} and Spliid, {Charlotte B.} and Yong Wang and Tobias Gustavsson and Sandoval, {Daniel R.} and Vidal-Calvo, {Elena Ethel} and Swati Choudhary and Agerbaek, {Mette {\O}.} and Kresten Lindorff-Larsen and Nielsen, {Morten A.} and Theander, {Thor G.} and Sharp, {Joshua S} and Clausen, {Thomas Mandel} and Pontus Gourdon and Ali Salanti",
year = "2021",
doi = "10.1038/s41467-021-23254-1",
language = "English",
volume = "12",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "nature publishing group",
number = "1",

}

RIS

TY - JOUR

T1 - Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding

AU - Wang, Kaituo

AU - Dagil, Robert

AU - Lavstsen, Thomas

AU - Misra, Sandeep K

AU - Spliid, Charlotte B.

AU - Wang, Yong

AU - Gustavsson, Tobias

AU - Sandoval, Daniel R.

AU - Vidal-Calvo, Elena Ethel

AU - Choudhary, Swati

AU - Agerbaek, Mette Ø.

AU - Lindorff-Larsen, Kresten

AU - Nielsen, Morten A.

AU - Theander, Thor G.

AU - Sharp, Joshua S

AU - Clausen, Thomas Mandel

AU - Gourdon, Pontus

AU - Salanti, Ali

PY - 2021

Y1 - 2021

N2 - Placental malaria can have severe consequences for both mother and child and effective vaccines are lacking. Parasite-infected red blood cells sequester in the placenta through interaction between parasite-expressed protein VAR2CSA and the glycosaminoglycan chondroitin sulfate A (CS) abundantly present in the intervillous space. Here, we report cryo-EM structures of the VAR2CSA ectodomain at up to 3.1 Å resolution revealing an overall V-shaped architecture and a complex domain organization. Notably, the surface displays a single significantly electropositive patch, compatible with binding of negatively charged CS. Using molecular docking and molecular dynamics simulations as well as comparative hydroxyl radical protein foot-printing of VAR2CSA in complex with placental CS, we identify the CS-binding groove, intersecting with the positively charged patch of the central VAR2CSA structure. We identify distinctive conserved structural features upholding the macro-molecular domain complex and CS binding capacity of VAR2CSA as well as divergent elements possibly allowing immune escape at or near the CS binding site. These observations will support rational design of second-generation placental malaria vaccines.

AB - Placental malaria can have severe consequences for both mother and child and effective vaccines are lacking. Parasite-infected red blood cells sequester in the placenta through interaction between parasite-expressed protein VAR2CSA and the glycosaminoglycan chondroitin sulfate A (CS) abundantly present in the intervillous space. Here, we report cryo-EM structures of the VAR2CSA ectodomain at up to 3.1 Å resolution revealing an overall V-shaped architecture and a complex domain organization. Notably, the surface displays a single significantly electropositive patch, compatible with binding of negatively charged CS. Using molecular docking and molecular dynamics simulations as well as comparative hydroxyl radical protein foot-printing of VAR2CSA in complex with placental CS, we identify the CS-binding groove, intersecting with the positively charged patch of the central VAR2CSA structure. We identify distinctive conserved structural features upholding the macro-molecular domain complex and CS binding capacity of VAR2CSA as well as divergent elements possibly allowing immune escape at or near the CS binding site. These observations will support rational design of second-generation placental malaria vaccines.

U2 - 10.1038/s41467-021-23254-1

DO - 10.1038/s41467-021-23254-1

M3 - Journal article

C2 - 34011972

VL - 12

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 2956

ER -

ID: 263030620