The structural basis for CD36 binding by the malaria parasite

Abstract

CD36 is a scavenger receptor involved in fatty acid metabolism, innate immunity and angiogenesis. It interacts with lipoprotein particles and facilitates uptake of long chain fatty acids. It is also the most common target of the PfEMP1 proteins of the malaria parasite, Plasmodium falciparum, tethering parasite-infected erythrocytes to endothelial receptors. This prevents their destruction by splenic clearance and allows increased parasitaemia. Here we describe the structure of CD36 in complex with long chain fatty acids and a CD36-binding PfEMP1 protein domain. A conserved hydrophobic pocket allows the hugely diverse PfEMP1 protein family to bind to a conserved phenylalanine residue at the membrane distal tip of CD36. This phenylalanine is also required for CD36 to interact with lipoprotein particles. By targeting a site on CD36 that is required for its physiological function, PfEMP1 proteins maintain the ability to tether to the endothelium and avoid splenic clearance.

Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria

“…Sequence classification has revealed conserved tandem arrangements of domains known as domain cassettes (DC) (Rask et al, 2010; Smith et al, 2000) and provided molecular insight into protein diversification. The N-terminal DBL-CIDR head structure has diverged between var groups, such that group B and C PfEMP1 encode CD36 binding properties (CIDRα2–6 domains) (Hsieh et al, 2016; Robinson et al, 2003) whereas group A proteins have diversified into those that bind endothelial protein C receptor (EPCR) (CIDRα1 domains) or non-EPCR binders (CIDRβ/γ/δ domains) (Lau et al., 2015; Turner et al, 2013). The latter group A subset is less well characterized, although some mediate rosetting of pRBCs with unparasitized RBCs (Ghumra et al, 2012).…”

Endothelial cell CD36 optimizes tissue fatty acid uptake

“…It was first linked to lipid metabolism when it was shown to function as a macrophage receptor for oxidized LDL (6) and as an adipocyte receptor/transporter for LCFAs (7). LCFA binding to the CD36 ectodomain is followed by FA transfer to the plasma membrane through an internal tunnel that runs the length of the protein, as shown by the crystal structure of the CD36-LCFA complex (8). CD36 also functions as a LCFA sensor, influencing activation of PPARs (9) and AMPK (10).…”

Intestinal CD36 and Other Key Proteins of Lipid Utilization: Role in Absorption and Gut Homeostasis

“…3). CrystallizedCD36 was also found in complex with long chain FA (palmitic and stearic acids) (67). The FA is thought to dock within a surface hydrophobic cavity that leads to the internal tunnel.…”