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

Sai Sundar Rajan Raghavan; Louise Turner; Rasmus W. Jensen; Nicolai Tidemand Johansen; Daniel Skjold Jensen; Pontus Gourdon; Jinqiu Zhang; Yong Wang; Thor Grundtvig Theander; Kaituo Wang; Thomas Lavstsen

doi:10.1016/j.str.2023.07.011

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

Sai Sundar Rajan Raghavan, Louise Turner, Rasmus W. Jensen, Nicolai Tidemand Johansen, Daniel Skjold Jensen, Pontus Gourdon, Jinqiu Zhang, Yong Wang, Thor Grundtvig Theander, Kaituo Wang, Thomas Lavstsen

Forskningsoutput: Tidskriftsbidrag › Artikel i vetenskaplig tidskrift › Peer review

Sammanfattning

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.

Originalspråk	engelska
Sidor (från-till)	1174-1183.e4
Tidskrift	Structure
Volym	31
Nummer	10
DOI	https://doi.org/10.1016/j.str.2023.07.011
Status	Published - 2023 okt. 5

Ämnesklassifikation (UKÄ)

Infektionsmedicin

FN:s Globala mål

Denna forskningsoutput relaterar till följande Globala mål

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10.1016/j.str.2023.07.011

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@article{209e485fe9e04ba0bf3986464c91007c,

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

abstract = "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.",

author = "{Rajan Raghavan}, {Sai Sundar} and Louise Turner and Jensen, {Rasmus W.} and Johansen, {Nicolai Tidemand} and Jensen, {Daniel Skjold} and Pontus Gourdon and Jinqiu Zhang and Yong Wang and Theander, {Thor Grundtvig} and Kaituo Wang and Thomas Lavstsen",

year = "2023",

month = oct,

day = "5",

doi = "10.1016/j.str.2023.07.011",

language = "English",

volume = "31",

pages = "1174--1183.e4",

journal = "Structure",

issn = "0969-2126",

publisher = "Cell Press",

number = "10",

}

TY - JOUR

T1 - Endothelial protein C receptor binding induces conformational changes to severe malaria-associated group A PfEMP1

AU - Rajan Raghavan, Sai Sundar

AU - Turner, Louise

AU - Jensen, Rasmus W.

AU - Johansen, Nicolai Tidemand

AU - Jensen, Daniel Skjold

AU - Gourdon, Pontus

AU - Zhang, Jinqiu

AU - Wang, Yong

AU - Theander, Thor Grundtvig

AU - Wang, Kaituo

AU - Lavstsen, Thomas

PY - 2023/10/5

Y1 - 2023/10/5

N2 - 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.

AB - 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.

U2 - 10.1016/j.str.2023.07.011

DO - 10.1016/j.str.2023.07.011

M3 - Article

C2 - 37582356

AN - SCOPUS:85172200717

SN - 0969-2126

VL - 31

SP - 1174-1183.e4

JO - Structure

JF - Structure

IS - 10

ER -

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

Sammanfattning

Ämnesklassifikation (UKÄ)

FN:s Globala mål

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