Characteristic features of the SERA multigene family in the malaria parasite

Abstract

Serine repeat antigen (SERA) is conserved among species of the genus Plasmodium. Sera genes form a multigene family and are generally tandemly clustered on a single chromosome. Although all Plasmodium species encode multiple sera genes, the number varies between species. Among species, the members share similar sequences and gene organization. SERA possess a central papain-like cysteine protease domain, however, in some members, the active site cysteine residue is substituted with a serine. Recent studies implicate this gene family in a number of aspects in parasite biology and induction of protective immune response. This review summarizes the current understanding on this important gene family in several Plasmodium species. The Plasmodium falciparum (Pf)-sera family, for example, consists of nine gene members. Unlike other multigene families in Plasmodium species, Pf-sera genes do not exhibit antigenic variation. Pf-sera5 nucleotide diversity is also low. Moreover, although Pf-sera5 is highly transcribed during the blood stage of malaria infection, and a large amount is released into the host blood following schizont rupture, in malaria endemic countries the sero-positive rates for Pf-SERA5 are low, likely due to Pf-SERA5 binding of host proteins to avoid immune recognition. As an antigen, the N-terminal 47 kDa domain of Pf-SERA5 is a promising vaccine candidate currently undergoing clinical trials. Pf-SERA5 and Pf-SERA6, as well as P. berghei (Pb)-SERA3, and Pb-SERA5, have been investigated for their roles in parasite egress. Two P. yoelii SERA, which have a serine residue at the protease active center, are implicated in parasite virulence. Overall, these studies provide insight that during the evolution of the Plasmodium parasite, the sera gene family members have increased by gene duplication, and acquired various functions that enable the parasite to survive and successfully maintain infection in the host.

A Plasmodium cysteine protease required for efficient transition from the liver infection stage

“…The cysteine-type SERA genes form three phylogenetically distinct groups [ 36 ]. Group one, represented by Pb SERA5 and Pf SERA8, in P .…”

“…The cysteine-type SERA genes form three phylogenetically distinct groups [36]. Group one, represented by PbSERA5 and PfSERA8, in P. berghei and P. falciparum, respectively, is required for egress of sporozoites from oocysts [15].…”

Structure of the Plasmodium falciparum PfSERA5 pseudo‐zymogen

“…12,13 Cysteine and serine protease and protease-like proteins, some of which accumulate inside the membranebound parasitophorous vacuole (PV) during the late trophozoite and schizont stages, play integral roles in erythrocytic development and in egress 7 ; these include falcipain cysteine proteases, 14 subtilisin serine proteases, 15,16 the upstream plasmepsin aspartic proteases, 17 chiefly plasmepsins IX and X (PMIX and PMX), 10 and the serine repeat antigen (SERA) family of proteins. Named for the presence of consecutive serine residues present within the protein sequence, the occurrence of the multigene SERA family has evolved via instances of gene duplication, 18 resulting in the presence of a number of SERA members existing in all Plasmodium species. Although the size of the family differs between species, all SERA members contain a conserved central papain-like domain.…”

“…Although the size of the family differs between species, all SERA members contain a conserved central papain-like domain. 18,19 Of the nine sequence similar members within P. falciparum (PfSERA1-9), those of PfSERA6-8 contain a conventional papain-like domain, with an archetypal catalytic triad (cysteine, histidine and aspartate residues). The remainder (PfSERA1-5 and -9), however, have this cysteine replaced by a serine.…”

“…Named for the presence of consecutive serine residues present within the protein sequence, the occurrence of the multigene SERA family has evolved via instances of gene duplication, 18 resulting in the presence of a number of SERA members existing in all Plasmodium species. Although the size of the family differs between species, all SERA members contain a conserved central papain‐like domain 18,19 . Of the nine sequence similar members within P. falciparum (PfSERA1‐9), those of PfSERA6‐8 contain a conventional papain‐like domain, with an archetypal catalytic triad (cysteine, histidine and aspartate residues).…”