PEST sequences in the malaria parasite Plasmodium falciparum: a genomic study.
BACKGROUND
Inhibitors of the protease calpain are known to have selectively toxic effects on Plasmodium falciparum. The enzyme has a natural inhibitor calpastatin and in eukaryotes is responsible for turnover of proteins containing short sequences enriched in certain amino acids (PEST sequences). The genome of P. falciparum was searched for this protease, its natural inhibitor and putative substrates.


METHODS
The publicly available P. falciparum genome was found to have too many errors to permit reliable analysis. An earlier annotation of chromosome 2 was instead examined. PEST scores were determined for all annotated proteins. The published genome was searched for calpain and calpastatin homologs.


RESULTS
Typical PEST sequences were found in 13% of the proteins on chromosome 2, including a surprising number of cell-surface proteins. The annotated calpain gene has a non-biological "intron" that appears to have been created to avoid an unrecognized frameshift. Only the catalytic domain has significant similarity with the vertebrate calpains. No calpastatin homologs were found in the published annotation.


CONCLUSIONS
A calpain gene is present in the genome and many putative substrates of this enzyme have been found. Calpastatin homologs may be found once the re-annotation is completed. Given the selective toxicity of calpain inhibitors, this enzyme may be worth exploring further as a potential drug target.
Mitchell
David
D
Department of Microbiology, Moyne Institute, Trinity College, Dublin 2, Republic of Ireland. dmitchel@tcd.ie
Bell
Angus
A
D000595:Amino Acid Sequence; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics; D002154:Calpain / Q000235:genetics; D015853:Cysteine Proteinase Inhibitors / Q000235:genetics; D030541:Databases, Genetic; D018503:Genome, Protozoan; D016778:Malaria, Falciparum / Q000235:genetics*; D010963:Plasmodium falciparum / Q000737:chemistry / Q000235:genetics*; D015800:Protozoan Proteins / Q000032:analysis / Q000235:genetics
D002135:Calcium-Binding Proteins; D015853:Cysteine Proteinase Inhibitors; D015800:Protozoan Proteins; C033668:calpastatin; D002154:Calpain