Calcium dependent protein kinases, absent in animals but found in apicomplexan parasites and specific plants, typically consist of a kinase domain with a calcium-binding CDPK Activation Domain (CAD) in the C-terminus. Often, the CAD is made up of a long flexible helix (CH1) followed by two pairs of EF-hands linked by another flexible helix (CH2). In Plasmodium falciparum, the parasite responsible for infecting humans with a lethal strain of malaria, there are five known CDPKs in the genome, including PfCDPK2, or PFF0520w.
Using the activated and inactivated structures of CDPKs from Toxoplasma and Cryptosporidium (3HZT, 3HX4, 3IGO), we have previously proposed that a model for the activation of CDPKs based on calcium-triggered refolding of the CAD from the state exemplified in 3HXT to the conformation in 3IGO [1, 2]. Here, we present the structure of the CAD domain alone from PfCDPK2, which provides a deeper understanding of the mechanism of refolding.
The CAD domain forms a dimer in solution in the absence of the kinase domain. For the most part, this domain is folded in the same manner as it is in the activated full length CDPK structure (3HX4, 3IGO).
