Engagement Rules That Underpin DBL-DARC Interactions for Ingress of Plasmodium knowlesi and Plasmodium vivax Into Human Erythrocytes

Abstract

Malaria parasite erythrocytic stages comprise of repeated bursts of parasites via cyclical invasion of host erythrocytes using dedicated receptor-ligand interactions. A family of erythrocyte-binding proteins from Plasmodium knowlesi (Pk) and Plasmodium vivax (Pv) attach to human Duffy antigen receptor for chemokines (DARC) via their Duffy binding-like domains (DBLs) for invasion. Here we provide a novel, testable and overarching interaction model that rationalizes even contradictory pieces of evidence that have so far existed in the literature on Pk/Pv-DBL/DARC binding determinants. We further address the conundrum of how parasite-encoded Pk/Pv-DBLs recognize human DARC and collate evidence for two distinct DARC integration sites on Pk/Pv-DBLs.

Global distribution of single amino acid polymorphisms in Plasmodium vivax Duffy-binding-like domain and implications for vaccine development efforts

“…One major SAAP (L379I) maps to the intervening structural spaces between Site1 and Site2 and contributes 10.4% of total SAAP instances. It is noted that four SAAPs-I277M, W349R (both minor SAAPs), S353T and T359R (both major SAAPs)-occurred within 5 Å of Site2, whereas only one major SAAP-I374M-was found to occur within 5 Å radius of Site1 indicating higher physico-chemical conservation of the local environment of Site1 over Site2 and its importance as a key DARC-binding region, in agreement with previously published studies [11,14,18,22,23,25,27,28]. Three major SAAPs-N372K, L379I (in Subdomain 2) and W392R (in Subdomain 3)-seem to be closely related as they occurred together in 43% of all the isolates analysed across different geographical regions.…”

“…Pv DBL and its Pk DBL orthologues are boomerang-shaped, monomeric structures with three distinct subdomains [ 11 , 23 ]. Pv DBL contains twelve cysteine residues that form intra-domain disulfide bonds and these are largely conserved within DBLs [ 11 , 24 , 25 ]. Of the three subdomains in Pv DBL, subdomain 1 has been shown to be dispensable for DBL–DARC interaction [ 11 , 14 ].…”

“…vivax Duffy-binding protein (PvDBP) is composed of seven regions/domains, has a molecular weight of approximately 140 kDa and is a type-1 integral membrane protein [5]. Region II of PvDBP (PvDBP-II) is known as the Duffy-binding-like domain (PvDBL) and this domain contains the critical DARC-binding motifs [9,[21][22][23][24][25]. PvDBL and its PkDBL orthologues are boomerang-shaped, monomeric structures with three distinct subdomains [11,23].…”

“…These two sites have been annotated based on comprehensive analyses of crystal structure information, mutagenesis studies and RBC-binding assays [11,18,22,23,[25][26][27][28][29][30][31][32]. The two sites contain conserved residues that are surface exposed and they probably play central roles in DARC binding via recognition of the sulfated tyrosines [11,14,23,25]. Site1 residues include K297, K301, R304 and K378, while K273, R274 and Q356 constitute Site2 [25].…”

“…The two sites contain conserved residues that are surface exposed and they probably play central roles in DARC binding via recognition of the sulfated tyrosines [11,14,23,25]. Site1 residues include K297, K301, R304 and K378, while K273, R274 and Q356 constitute Site2 [25]. DARC binding is facilitated via atomic interactions of residues within Site1 and Site2 with post-translationally modified (sulfated) Tyr41 and Tyr30 on DARC peptide, respectively [25,28].…”