Crystal Structure of the Plasmodium falciparum Apicoplast DNA Polymerase

Abstract

Almost half of the world's population is at risk of malaria. The parasite Plasmodium falciparum from the phylum Apicomplexa is the leading cause of malaria infection in humans. Members of Apicomplexa contain a unique and essential organelle called the apicoplast. The apicoplast maintains its own 35 kb genome, which must undergo replication and repair. An A‐family polymerase, apPOL, has been identified as the apicoplast replicative DNA polymerase. Members of A‐family are divided into five subgroups, of which only members of the clade containing ‘typical’ A‐family DNA polymerases such as E. coli Pol I (from which the A‐family is named) and Taq polymerase have been well characterized. Currently, no structural information is available for apPOL, and its closest homolog, the Klenow fragment of E. coli Pol I, shares only 28% sequence identity. Here we report the crystal structure of P. falciparum apPOL, the first atypical A‐family polymerase to be structurally characterized. There are significant structural differences between apPOL and Klenow, primarily in the addition of 46 residues at the N‐terminus of the exonuclease domain. This region may play a role in the recognition of the DNA substrate and possibly influence the activity of the exonuclease active site. Since apPOL has no direct orthologs to mammalian polymerases, P. falciparum apPOL is an attractive anti‐malarial drug target that provides structural and biochemical insight into a poor characterized subgroup of A‐family polymerases.