Endothelial protein C receptor binding induces conformational changes to severe malaria-associated group A PfEMP1

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Severe Plasmodium falciparum malaria infections are caused by microvascular sequestration of parasites binding to the human endothelial protein C receptor (EPCR) via the multi-domain P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion ligands. Using cryogenic electron microscopy (Cryo-EM) and PfEMP1 sequence diversity analysis, we found that group A PfEMP1 CIDRα1 domains interact with the adjacent DBLα1 domain through central, conserved residues of the EPCR-binding site to adopt a compact conformation. Upon EPCR binding, the DBLα1 domain is displaced, and the EPCR-binding helix of CIDRα1 is turned, kinked, and twisted to reach a rearranged, stable EPCR-bound conformation. The unbound conformation and the required transition to the EPCR-bound conformation may represent a conformational masking mechanism of immune evasion for the PfEMP1 family.

OriginalsprogEngelsk
TidsskriftStructure
Vol/bind31
Udgave nummer10
Sider (fra-til)1174-1183.e4
ISSN0969-2126
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
We are grateful to the Core Facility for Integrated Microscopy (CFIM), University of Copenhagen for providing support during screening and data collection. We also thank the Swedish National Cryo-EM facility, Science for Life Laboratory, Sweden for supporting data collection. We thank Prof. Anja Fuglsang, PLEN, University of Copenhagen for providing access to the BLI instrument. We are thankful for the access to computational resources from the Information Technology Center and State Key Lab of CAD&CG, Zhejiang University. SSRR, LT, RWJ, and TL were funded by The Lundbeck Foundation (R344-2020-934), the Independent Research Fund Denmark (9039-00285A), Kirsten & Freddy Johansens Fond and BWJ holding fund. NTJ was funded by Villum Fonden, Denmark (35955). YW received support from the National Key Research and Development Program of China (No. 2021YFF1200404) and the Fundamental Research Funds for the Central Universities in China (No. K20220228). Conceptualization, S.S.R.R. L.T. T.G.T. K.T.W. and T.L.; Methodology, S.S.R.R. K.T.W. and T.L.; Software, S.S.R.R. and K.T.W.; Validation, D.S.J. and N.T.J.; Investigation, S.S.R.R. and K.T.W.; Formal Analysis, S.S.R.R. J.Q.Z. Y.W. K.T.W. and T.L.; Resources, P.G. L.T. and Y.W.; Data Curation, S.S.R.R. K.T.W. and T.L.; Writing—Original Draft, S.S.R.R. and T.L.; Writing—Review & Editing, S.S.R.R. L.T. N.T.J. T.G.T. Y.W. K.T.W. P.G. and T.L.; Visualization, S.S.R.R. Y.W. and T.L.; Supervision, L.T. K.T.W. and T.L.; Project Administration, T.L.; Funding Acquisition, T.L. The authors declare no competing interests. We support inclusive, diverse and equitable conduct of research.

Funding Information:
We are grateful to the Core Facility for Integrated Microscopy (CFIM), University of Copenhagen for providing support during screening and data collection. We also thank the Swedish National Cryo-EM facility , Science for Life Laboratory , Sweden for supporting data collection. We thank Prof. Anja Fuglsang, PLEN, University of Copenhagen for providing access to the BLI instrument. We are thankful for the access to computational resources from the Information Technology Center and State Key Lab of CAD&CG, Zhejiang University. SSRR, LT, RWJ, and TL were funded by The Lundbeck Foundation ( R344-2020-934 ), the Independent Research Fund Denmark ( 9039-00285A ), Kirsten & Freddy Johansens Fond and BWJ holding fund . NTJ was funded by Villum Fonden , Denmark ( 35955 ). YW received support from the National Key Research and Development Program of China (No. 2021YFF1200404 ) and the Fundamental Research Funds for the Central Universities in China (No. K20220228 ).

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© 2023 Elsevier Ltd

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