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

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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; Lindorff-Larsen, Kresten; Nielsen, Morten A.; Theander, Thor G.; Sharp, Joshua S.; Clausen, Thomas Mandel; Gourdon, Pontus; Salanti, Ali.

In: Nature Communications, Vol. 12, 2956, 12.2021.

Research output: Contribution to journalArticle

Harvard

Wang, K, Dagil, R, Lavstsen, T, Misra, SK, Spliid, CB, Wang, Y, Gustavsson, T, Sandoval, DR, Vidal-Calvo, EE, Choudhary, S, Agerbaek, M, 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, 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., 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, [2956]. https://doi.org/10.1038/s41467-021-23254-1

CBE

Wang K, Dagil R, Lavstsen T, Misra SK, Spliid CB, Wang Y, Gustavsson T, Sandoval DR, Vidal-Calvo EE, Choudhary S, Agerbaek M, 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. 12:Article 2956. https://doi.org/10.1038/s41467-021-23254-1

MLA

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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 ; 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.

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

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 - 2021/12

Y1 - 2021/12

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 - Article

C2 - 34011972

AN - SCOPUS:85106050149

VL - 12

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 2956

ER -