Abstract
Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) and Knob-associated Histidine-rich Protein (KAHRP) are directly linked to malaria pathology. PfEMP1 and KAHRP cluster on protrusions (knobs) on the P. falciparum-infected erythrocyte surface and enable pathogenic cytoadherence of infected erythrocytes to the host microvasculature, leading to restricted blood flow, oxygen deprivation and damage of tissues. Here we characterize the interactions of PfEMP1 and KAHRP with host erythrocyte spectrin using biophysical, structural and computational approaches. These interactions assist knob formation and, thus, promote cytoadherence. We show that the folded core of the PfEMP1 cytosolic domain interacts broadly with erythrocyte spectrin but shows weak, residue-specific preference for domain 17 of α spectrin, which is proximal to the erythrocyte cytoskeletal junction. In contrast, a protein sequence repeat region in KAHRP preferentially associates with domains 10–14 of β spectrin, proximal to the spectrin–ankyrin complex. Structural models of PfEMP1 and KAHRP with spectrin combined with previous microscopy and protein interaction data suggest a model for knob architecture.
Highlights
Malaria remains one of the most lethal global diseases, causing an estimated 429,000 deaths in 2016 [1]
Formation of cytoadherent knobs on the surface of P. falciparum infected erythrocytes correlates with malaria pathology
Relevant to malaria pathology is the formation of protrusions on the P. falciparum-infected erythrocyte surface, known as knobs [9], that allow infected cells to adhere to uninfected erythrocytes and the microvascular endothelium
Summary
Malaria remains one of the most lethal global diseases, causing an estimated 429,000 deaths in 2016 [1]. The majority of these deaths are attributed to infections by the Plasmodium falciparum parasite (reviewed in [2]). Relevant to malaria pathology is the formation of protrusions on the P. falciparum-infected erythrocyte surface, known as knobs [9], that allow infected cells to adhere to uninfected erythrocytes and the microvascular endothelium. Cytoadherence of infected erythrocytes increases malaria severity by removing infected cells from circulation thereby allowing them to avoid splenic passage and clearance (reviewed in [10]). Understanding the molecular mechanisms supporting knob formation in infected erythrocytes holds the potential of alleviating malaria severity by disabling parasite-induced cytoadherence
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