Genomic organization, structure and possible function of histidine-rich proteins of malaria parasites

Abstract

The current status of histidine-rich proteins in malaria parasites with regard to their genomic organization, protein structure and function is discussed, one of such protein present in an avian malaria parasite Plasmodium lophurae contains about 73% histidine and called as HRP (histidine-rich protein). Among human malaria parasites, in Plasmodium falciparum, only three such proteins have been described, namely knob protein also known as knob associated histidine-rich protein (KP or KAHRP), soluble histidine-alanine rich protein (soluble HARP or PfHRP II) and small histidine-alanine rich protein (SHARP) containing 8, 35 and 30% histidine contents respectively. With rapid emergence of powerful tools in molecular biology the genes of all these histidine-rich proteins have been cloned and sequenced within a short period of time. The genomic organizations of all these proteins are very much similar to each other, in each case the gene contains a signal peptide coding sequence (exon 1) followed by an intron. This intron is followed by the main coding region (exon 2) which has no further intervening sequences. In the main coding region of each gene, the histidine-rich sequences start after 25–30 amino acids from N-terminal end (75–90 nucleotides from 5' in exon 2). All the three histidine-rich proteins of P. falciparum share some homology with the HRP of P. lophurae; they all cross react with anti HRP and incorporate higher amount of exogenous histidine. The relationship between KP and HRP resides in the repeated polyhistidine sequences, (His) 6–9, from the core of the multiple tandem repeats of HRP, whereas, the peptide Ala-His-His is commonly shared by HRP and two other proteins of P. falciparum (soluble HARP and SHARP). There is no common homology between KP and the other two proteins of the same parasite, P. falciparum, though each protein is rich in histidine. However, the later two proteins (soluble HARP and SHARP) of P. falciparum are highly cross-reactive and this homology leads to the conclusion that both genes have arisen by duplication and divergence from a common ancestral gene. All these histidine-rich proteins so far known in malaria parasites are immunogenic. However, the exact role of these proteins with regard to the survival of the parasite is not clear, except for knob protein which induces knob formation on the surface of parasitized erythrocytes, leading to their sequestration along with venous endothelium. Most likely, the other histidine-rich proteins of malaria parasites may be acting as a metal detoxifying agent because histidine has a higher metal binding capacity. Further support comes from the fact that HRP of P. lophurae and soluble HARP of P. falciparum are released (discarded) into the surrounding medium (plasma) by the parasites. Several other histidine-rich proteins of malaria parasites may be discovered in the near future as the other Plasmodium species remains to be tested.