Abstract
Calcium dependent protein kinases are unique to plants and certain parasites and comprise an N-terminal segment and a kinase domain that is regulated by a C-terminal calcium binding domain. Since the proteins are not found in man they are potential drug targets. We have characterized the calcium binding lobes of the regulatory domain of calcium dependent protein kinase 3 from the malaria parasite Plasmodium falciparum. Despite being structurally similar, the two lobes differ in several other regards. While the monomeric N-terminal lobe changes its structure in response to calcium binding and shows global dynamics on the sub-millisecond time-scale both in its apo and calcium bound states, the C-terminal lobe could not be prepared calcium-free and forms dimers in solution. If our results can be generalized to the full-length protein, they suggest that the C-terminal lobe is calcium bound even at basal levels and that activation is caused by the structural reorganization associated with binding of a single calcium ion to the N-terminal lobe.
Highlights
Malaria is a life-threatening disease caused by apicomplexan parasites of the Plasmodium family
The individual domains of calmodulin like domain (CLD) adopt solution structures that are typical of EFhand proteins and the calcium bound forms are very similar to the corresponding fragments of the crystal structure of calcium bound CDPK activation domain (CAD) as gauged by the CS-Rosetta structural ensembles
If the results can be generalized to full-length pfCDPK3 they could mean that CLD C-lobe binds calcium immediately after synthesis and does not change its structure in response to fluctuating calcium levels as has been proposed for CPK-1 from Arabidopsis thaliana [9]
Summary
Malaria is a life-threatening disease caused by apicomplexan parasites of the Plasmodium family. Despite progress in treatment and prevention strategies there are still around 200 million cases of malaria resulting in approximately half a million deaths annually [1]. It is of vital interest to characterize the Plasmodium proteome in search for additional drug targets. Calcium is required for vital functions such as protein secretion, host cell invasion and parasite motility [2]. Cytosolic calcium is regulated by several mechanisms and elevated levels trigger activation of pathways that are gated by calcium sensing proteins. In plants and certain protozoa, including apicomplexan parasites, one such class of proteins is the calcium dependent protein kinases (CDPKs). In P. falciparum, there are seven CDPKs termed pfCDPK1 through pfCDPK7 [3]
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