Plasmodium 6-Cysteine Proteins: Functional Diversity, Transmission-Blocking Antibodies and Structural Scaffolds

Abstract

The 6-cysteine protein family is one of the most abundant surface antigens that are expressed throughout the Plasmodium falciparum life cycle. Many members of the 6-cysteine family have critical roles in parasite development across the life cycle in parasite transmission, evasion of the host immune response and host cell invasion. The common feature of the family is the 6-cysteine domain, also referred to as s48/45 domain, which is conserved across Aconoidasida. This review summarizes the current approaches for recombinant expression for 6-cysteine proteins, monoclonal antibodies against 6-cysteine proteins that block transmission and the growing collection of crystal structures that provide insights into the functional domains of this protein family.

Proteome-wide comparison of tertiary protein structures reveal extensive molecular mimicry inPlasmodium-human interactions

“…Here, we present the biological relevance of a subset of these proteins. The four 6-cysteine proteins present in these 13 proteins are one of the most abundant surface antigens in the P. falciparum (Lyons et al, 2022) and have been attributed to virulence in related parasites (Wasmuth et al, 2012). These are promising candidates for mediators of host-parasite interactions.…”

“…Members of this gene-family are expressed in multiple stages of the P. falciparum life-cycle in both the hosts (Lyons et al, 2022). Interestingly, while several members of this family have been implicated in critical functions like immune-evasion and host cell invasion, the precise roles for several of these proteins, like P12, P12p, P38, and P41, remain unknown (Lyons et al, 2022). Therefore, our structure-similarity-based approach improved our knowledge of how some of these proteins contribute to immune evasion, by identifying a potential binding-partner (IgM) and function for these proteins.…”

“…One promising example involves multiple members of the 6-cysteine proteins found in P. falciparum . Members of this gene-family are expressed in multiple stages of the P. falciparum life-cycle in both the hosts (Lyons et al, 2022). Interestingly, while several members of this family have been implicated in critical functions like immune-evasion and host cell invasion, the precise roles for several of these proteins, like P12, P12p, P38, and P41, remain unknown (Lyons et al, 2022).…”

Development of an anti-Pfs230 monoclonal antibody as a Plasmodium falciparum gametocyte blocker

“…Cocktails of different antibodies or bispecific molecules could serve this specific purpose and render this strategy more effective and long-lasting ( 35 ). In the recent past, panels of monoclonal antibodies targeting Pfs230 with a different range of affinity have been developed by various research groups, confirming the need to generate new reagents towards this antigen ( 36 ).…”

Genomics of Plasmodium vivax in Colombia: evidence of local bottle-necking and inter-country connectivity in the Americas

“…6d). The Colombian signals re ect a variety of putative drivers including a pyridoxine biosynthesis protein PDX2, a conserved oligomeric Golgi complex subunit 4 protein, 6-cysteine proteins P12 and P47, whose P. falciparum orthologs are involved in host immune evasion, a metacaspase-2, whose ortholog has a role in malaria transmission, and a conserved Plasmodium protein with unknown function 43,44 . Four signals were observed against Indonesia, with one region representing selection within Colombia (Fig.…”