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

Raghavan, Sai Sundar Rajan; Turner, Louise; Jensen, Rasmus Weisel; Johansen, Nicolai Tidemand; Jensen, Dan Børge; Gourdon, Pontus; Zhang, Jinqiu; Wang, Yong; Theander, Thor G.; Wang, Kaituo; Lavstsen, Thomas

doi:10.1016/j.str.2023.07.011

Cited by 5 publications

(12 citation statements)

References 40 publications

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“…Furthermore, biolayer interferometry analyses showed that C7 and C74 Fabs bound CIDRα1 domains with high affinity whether presented individually or within their N-terminal domain complex (Figure S4B-C). Both Fabs exhibited similar on-rate kinetics and very low dissociation rates, mimicking the kinetics of EPCR binding to CIDRα1 [30,31].…”

Section: Broadly Reactive Mabs Bind Cidrα1 and Multi-domain Pfemp1 Wi...mentioning

confidence: 80%

“…In native PfEMP1, the CIDRα1 domain, its flanking DBLα domain, and the N-terminal segment (NTS) comprise the PfEMP1 N-terminal domain complex (Figure 1A). The DBLα and CIDRα1 domains interact with each other through central residues of the EPCR binding site on CIDRα1 to form a compact protein structure [30]. As a result, the EPCR-binding site is partially hidden in the unbound PfEMP1.…”

Section: Broadly Reactive Mabs Bind Cidrα1 and Multi-domain Pfemp1 Wi...mentioning

confidence: 99%

“…As a result, the EPCR-binding site is partially hidden in the unbound PfEMP1. When EPCR binds to CIDRα1, it displaces the DBLα domain and induces a conformational change to CIDRα1 by twisting and turning the EPCR-binding (EB) helix and the EPCR-binding supporting (EBS) helix [30]. Since the mAbs identified here were isolated using single CIDRα1domains, we assessed their ability to bind to a panel of recombinant multi-domain and full-length ectodomain PfEMP1 proteins and inhibit their interaction with EPCR.…”

Section: Broadly Reactive Mabs Bind Cidrα1 and Multi-domain Pfemp1 Wi...mentioning

confidence: 99%

“…EPCR-binding CIDRα1 domains divide into subclasses CIDRα1.1 and CIDRα1.4 -1.8 and share on average only ~60% of their 251 amino acids [29]. Structural studies of CIDRα1 domains in complex with EPCR show that despite this extensive sequence diversity, the CIDRα1 fold and the surface chemistry of the EPCR-binding site is conserved in order to retain the capacity to bind to EPCR [6,30]. We hypothesize that the structural and chemical constraints on the CIDRα1 domain, necessary for its binding to EPCR, may also enable antibody binding to many or even all CIDRα1 variants.…”

Section: Introductionmentioning

confidence: 99%

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Broadly inhibitory antibodies against severe malaria virulence proteins

Reyes,

Raghavan,

Hurlburt

et al. 2024

Preprint

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Plasmodium falciparum pathology is driven by the accumulation of parasite-infected erythrocytes in microvessels. This process is mediated by the parasite's polymorphic erythrocyte membrane protein 1 (PfEMP1) adhesion proteins. A subset of PfEMP1 variants that bind human endothelial protein C receptor (EPCR) through their CIDRα1 domains is responsible for severe malaria pathogenesis. A longstanding question is whether individual antibodies can recognize the large repertoire of circulating PfEMP1 variants. Here, we describe two broadly reactive and binding-inhibitory human monoclonal antibodies against CIDRα1. The antibodies isolated from two different individuals exhibited a similar and consistent EPCR-binding inhibition of 34 CIDRα1 domains, representing five of the six subclasses of CIDRα1. Both antibodies inhibited EPCR binding of both recombinant full-length and native PfEMP1 proteins as well as parasite sequestration in bioengineered 3D brain microvessels under physiologically relevant flow conditions. Structural analyses of the two antibodies in complex with two different CIDRα1 antigen variants reveal similar binding mechanisms that depend on interactions with three highly conserved amino acid residues of the EPCR-binding site in CIDRα1. These broadly reactive antibodies likely represent a common mechanism of acquired immunity to severe malaria and offer novel insights for the design of a vaccine or treatment targeting severe malaria.

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Section: Broadly Reactive Mabs Bind Cidrα1 and Multi-domain Pfemp1 Wi...mentioning

confidence: 80%

Section: Broadly Reactive Mabs Bind Cidrα1 and Multi-domain Pfemp1 Wi...mentioning

confidence: 99%

Section: Broadly Reactive Mabs Bind Cidrα1 and Multi-domain Pfemp1 Wi...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Broadly inhibitory antibodies against severe malaria virulence proteins

Reyes,

Raghavan,

Hurlburt

et al. 2024

Preprint

Self Cite

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“…PfEMP1-receptor binding and neutralising antibody mechanisms are increasingly being understood on a structural level and are relevant to understand malaria pathology and effectivity of the immune response in patients (Rajan Raghavan et al, 2023; Reyes et al, 2024). The straight forward capacity to generate cytoadherent parasite lines uniformly expressing a single PfEMP1 of interest opens up approaches to study receptor-binding as well as antibody-binding and inhibition using native as well as modified PfEMP1.…”

Section: Discussionmentioning

confidence: 99%

A system for functional studies of the major virulence factor of malaria parasites

Cronshagen,

Allweier,

Mesén-Ramírez

et al. 2024

Preprint

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PfEMP1 is a variable antigen displayed on red blood cells (RBCs) infected with the malaria parasite Plasmodium falciparum. PfEMP1 mediates binding of the infected cell to the endothelium of blood vessels, a major cause of severe manifestations of malaria. Each parasite encodes ~60 different PfEMP1 variants of which only one is expressed at a time and switching between variants underlies immune evasion in the host and variant-specific severity of disease. PfEMP1 expression heterogeneity between parasites complicates its study and hampers genetic modification approaches as in many cells the modified locus is not expressed. Here we used selection linked integration to generate parasites all expressing the same PfEMP1 variant and permitting genomic modification of the expressed locus. Using this system, we study PfEMP1 trafficking, generate cell lines binding to all major endothelial receptors, survey the protein environment from functional PfEMP1 in the host cell and identify new proteins needed for PfEMP1 mediated sequestration. Overall, these approaches facilitate the study of the molecular and cellular biology of the key virulence factor of malaria parasites.

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Host receptor binding induces conformational changes in a PfEMP1 protein

Ma,

Tolia

2023

Structure

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

Cited by 5 publications

References 40 publications

Broadly inhibitory antibodies against severe malaria virulence proteins

Broadly inhibitory antibodies against severe malaria virulence proteins

A system for functional studies of the major virulence factor of malaria parasites

Host receptor binding induces conformational changes in a PfEMP1 protein

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