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- Title
Novel insights into the regulation of malarial calcium-dependent protein kinase 1.
- Authors
Ahmed, Anwar; Gaadhe, Kavita; Sharma, Guru Prasad; Kumar, Narendra; Neculai, Mirela; Hui, Raymond; Mohanty, Debasisa; Sharma, Pushkar
- Abstract
Calcium-dependent protein kinases (CDPKs) are major effectors of calcium signaling in apicomplexan parasites like Toxoplasma and Plasmodium and control important processes of the parasite life cycle. Despite recently reported crystal structures of Toxoplasma gondii (Tg)CDPKs, several important questions about their regulation remain unanswered. Plasmodiumfalciparum (Pf)CDPK1 has emerged as a key player in the life cycle of the malaria parasite, as it may be involved in the invasion of the host cells. Molecular modeling and site-directed mutagenesis studies on PfCDPK1 suggested that several residues in the regula- tory domain play a dual role, as they seem to contribute to the stabilization of both the active and inactive kinase. Mass spectrometry revealed that PfCDPK1 was autophosphorylated at several sites; some of these were placed at strategic locations and therefore were found to be critical for kinase activation. The N-terminal extension of PfCDPK1 was found to be important for Pfl:DPK1 activation. Unexpectedly, an ATP binding site in the NTE of PfCDPK1 was identified. Our studies highlight several novel features of Pfl2DPK1 regulation, which may be shared by other members of the CDPK family. These findings may also aid design of inhibitors against these important targets, which are absent from the host.
- Subjects
CALCIUM-dependent protein kinase; APICOMPLEXA; AUTOPHOSPHORYLATION; CALCIUM; TOXOPLASMA gondii; MALARIA
- Publication
FASEB Journal, 2012, Vol 26, Issue 8, p3212
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.12-203877