Structure of the Regulatory Apparatus of a Calcium-dependent Protein Kinase (CDPK): A Novel Mode of Calmodulin-target Recognition

Chandran, Vidya; Stollar, Elliott J.; Lindorff‐Larsen, Kresten; Harper, Jeffrey F.; Chazin, Walter J.; Dobson, Christopher M.; Luisi, Ben F.; Christodoulou, John

doi:10.1016/j.jmb.2005.11.093

Cited by 62 publications

(44 citation statements)

References 40 publications

(37 reference statements)

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“…The template model used was CLD-JD of AtCPK-1, which was crystallized as a dimer. The J-domain helices from the two monomers were swapped with each other in this structure (21). Therefore, the initial homology model generated for the complementary CLD-J domain for PfCDPK4 was also a dimer.…”

Section: Methodsmentioning

confidence: 99%

Dissection of Mechanisms Involved in the Regulation of Plasmodium falciparum Calcium-dependent Protein Kinase 4

Ranjan

Ahmed

Gourinath

et al. 2009

Journal of Biological Chemistry

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Recent studies have demonstrated that calcium-dependent protein kinases (CDPKs) are used by calcium to regulate a variety of biological processes in the malaria parasite Plasmodium. CDPK4 has emerged as an important enzyme for parasite development, because its gene disruption in rodent parasite Plasmodium berghei causes major defects in sexual differentiation of the parasite (Billker, O., Dechamps, S., Tewari, R., Wenig, G., Franke-Fayard, B., and Brinkmann, V. (2004) Cell 117, 503-514). Despite these findings, it is not very clear how PfCDPK4 or any other PfCDPK is regulated by calcium at the molecular level. We report the biochemical characterization and elucidation of molecular mechanisms involved in the regulation of PfCDPK4. PfCDPK4 was detected on gametocyte periphery, and its activity in the parasite was regulated by phospholipase C. Even though the Junction Domain (JD) of PfCDPK4 shares moderate sequence homology with that of the plant CDPKs, it plays a pivotal role in PfCDPK4 regulation as previously reported for some plant CDPKs. The regions of the J-domain involved in interaction with both the kinase domain and the calmodulinlike domain were mapped. We propose a model for PfCDPK regulation by calcium, which may also prove useful for design of inhibitors against PfCDPK4 and other members of the PfCDPK family.

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Section: Methodsmentioning

confidence: 99%

Dissection of Mechanisms Involved in the Regulation of Plasmodium falciparum Calcium-dependent Protein Kinase 4

Ranjan

Ahmed

Gourinath

et al. 2009

Journal of Biological Chemistry

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“…Most importantly, CDPKs are absent from mammalian hosts. Structural studies on their mechanism of intramolecular activation showed that the N-terminal lobe of the calmodulin-like domain functions as the calcium sensor that triggers activation [52,53]. As shown with the T. gondii CDPK1 orthologue (TgCDPK1), activation of the enzyme upon calcium binding occurs through a large conformational change.…”

Section: The Camk Groupmentioning

confidence: 99%

The kinomes of apicomplexan parasites

Miranda‐Saavedra

Gabaldón

Barton

et al. 2012

Microbes and Infection

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Protein phosphorylation plays a fundamental role in the biology and invasion strategies of apicomplexan parasites. Many apicomplexan protein kinases are substantially different from their mammalian orthologues, and thus constitute a landscape of potential drug targets. Here, we integrate genomic, biochemical, genetic and evolutionary information to provide an integrated and up-to-date analysis of twelve apicomplexan kinomes. All kinome sequences are available through the Kinomer database.2

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“…Studies of plant CDPKs suggest that the key mechanism of regulation is inhibition of the KD by the junction region preceding the EF hands, predicted to act as a pseudosubstrate (7,8). The junction region interacts with the CaM-LD, and Ca 2+ binding alters this interaction, presumably to relieve inhibition of the KD (9,10). Structures of TgCDPK1 corroborated these predictions (11,12) and showed the extreme Ca 2+ -dependent rearrangement of the CaM-LD, which warranted its distinction as a new regulatory domain, dubbed the CDPK activation domain (CAD) (11).…”

mentioning

confidence: 99%

Allosteric activation of apicomplexan calcium-dependent protein kinases

Ingram

Knockenhauer

Markus

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Calcium-dependent protein kinases (CDPKs) comprise the major group of Ca 2+ -regulated kinases in plants and protists. It has long been assumed that CDPKs are activated, like other Ca 2+ -regulated kinases, by derepression of the kinase domain (KD). However, we found that removal of the autoinhibitory domain from Toxoplasma gondii CDPK1 is not sufficient for kinase activation. From a library of heavy chain-only antibody fragments (VHHs), we isolated an antibody (1B7) that binds TgCDPK1 in a conformation-dependent manner and potently inhibits it. We uncovered the molecular basis for this inhibition by solving the crystal structure of the complex and simulating, through molecular dynamics, the effects of 1B7-kinase interactions. In contrast to other Ca 2+ -regulated kinases, the regulatory domain of TgCDPK1 plays a dual role, inhibiting or activating the kinase in response to changes in Ca 2+ concentrations. We propose that the regulatory domain of TgCDPK1 acts as a molecular splint to stabilize the otherwise inactive KD. This dependence on allosteric stabilization reveals a novel susceptibility in this important class of parasite enzymes.calcium-dependent protein kinase | kinase activation | VHH

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Structure of the Regulatory Apparatus of a Calcium-dependent Protein Kinase (CDPK): A Novel Mode of Calmodulin-target Recognition

Cited by 62 publications

References 40 publications

Dissection of Mechanisms Involved in the Regulation of Plasmodium falciparum Calcium-dependent Protein Kinase 4

Dissection of Mechanisms Involved in the Regulation of Plasmodium falciparum Calcium-dependent Protein Kinase 4

The kinomes of apicomplexan parasites

Allosteric activation of apicomplexan calcium-dependent protein kinases

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