scholarly journals Phosphoinositide Metabolism Links cGMP-Dependent Protein Kinase G to Essential Ca2+ Signals at Key Decision Points in the Life Cycle of Malaria Parasites

PLoS Biology ◽  
2014 ◽  
Vol 12 (3) ◽  
pp. e1001806 ◽  
Author(s):  
Mathieu Brochet ◽  
Mark O. Collins ◽  
Terry K. Smith ◽  
Eloise Thompson ◽  
Sarah Sebastian ◽  
...  
Keyword(s):  
Life Cycle ◽  
Protein Kinase ◽  
Protein Kinase G ◽  
Phosphoinositide Metabolism ◽  
Dependent Protein Kinase ◽  
Malaria Parasites ◽  
Cgmp Dependent Protein Kinase ◽  
Decision Points ◽  
Dependent Protein

scholarly journals Gametogenesis in Malaria Parasites Is Mediated by the cGMP-Dependent Protein Kinase

PLoS Biology ◽  
2008 ◽  
Vol 6 (6) ◽  
pp. e139 ◽  
Author(s):  
Louisa McRobert ◽  
Cathy J Taylor ◽  
Wensheng Deng ◽  
Quinton L Fivelman ◽  
Ross M Cummings ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Dependent Protein Kinase ◽  
Malaria Parasites ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

scholarly journals A multipass membrane protein interacts with the cGMP-dependent protein kinase to regulate critical calcium signals in malaria parasites

2020 ◽  
Author(s):  
Aurélia C. Balestra ◽  
Konstantinos Koussis ◽  
Natacha Klages ◽  
Steven A. Howell ◽  
Helen R. Flynn ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Membrane Protein ◽  
Calcium Channels ◽  
Disease Transmission ◽  
Calcium Signals ◽  
Dependent Protein Kinase ◽  
Malaria Parasites ◽  
Major Function ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

AbstractIn malaria parasites, all cGMP-dependent signalling is mediated through a single cGMP-dependent protein kinase (PKG), a major function of which is to control essential calcium signals. However, how PKG transmits these signals in the absence of known second messenger-dependent calcium channels or scaffolding proteins is unknown. Here we identify a polytopic membrane protein, ICM1, with homology to transporters and calcium channels that is tightly-associated with PKG in both Plasmodium falciparum asexual blood stages and P. berghei gametocytes. Phosphoproteomic analyses in both Plasmodium species reveal multiple ICM1 phosphorylation events dependent upon PKG activity. Stage-specific depletion of P. berghei ICM1 blocks gametogenesis due to the inability of mutant parasites to mobilise intracellular calcium upon PKG activation, whilst conditional loss of P. falciparum ICM1 results in reduced calcium mobilisation, defective egress and lack of invasion. Our findings provide new insights into atypical calcium homeostasis in malaria parasites essential for pathology and disease transmission.

scholarly journals Targeting the Malaria Parasite cGMP-Dependent Protein Kinase to Develop New Drugs

2020 ◽  
Vol 11 ◽  
Author(s):  
David A. Baker ◽  
Alexios N. Matralis ◽  
Simon A. Osborne ◽  
Jonathan M. Large ◽  
Maria Penzo
Keyword(s):  
Life Cycle ◽  
Protein Kinase ◽  
Malaria Parasite ◽  
Public Health Problem ◽  
Major Public Health Problem ◽  
Parasite Life Cycle ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Cgmp Signaling ◽  
Dependent Protein

The single-celled apicomplexan parasite Plasmodium falciparum is responsible for the majority of deaths due to malaria each year. The selection of drug resistance has been a recurring theme over the decades with each new drug that is developed. It is therefore crucial that future generations of drugs are explored to tackle this major public health problem. Cyclic GMP (cGMP) signaling is one of the biochemical pathways that is being explored as a potential target for new antimalarial drugs. It has been shown that this pathway is essential for all of the key developmental stages of the complex malaria parasite life cycle. This gives hope that targeting cGMP signaling might give rise to drugs that treat disease, block its transmission and even prevent the establishment of infection. Here we review previous work that has been carried out to develop and optimize inhibitors of the cGMP-dependent protein kinase (PKG) which is a critical regulator of the malaria parasite life cycle.

scholarly journals Discovery of isoxazolyl-based inhibitors of Plasmodium falciparum cGMP-dependent protein kinase

2020 ◽  
Vol 11 (1) ◽  
pp. 98-101 ◽  
Author(s):  
Shams Ul Mahmood ◽  
Huimin Cheng ◽  
Sreedhar R. Tummalapalli ◽  
Ramappa Chakrasali ◽  
Rammohan R. Yadav Bheemanaboina ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Life Cycle ◽  
Protein Kinase ◽  
Multiple Roles ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

The cGMP-dependent protein kinase in Plasmodium falciparum (PfPKG) plays multiple roles in the life cycle of the parasite.

scholarly journals Structures of the cGMP-dependent protein kinase in malaria parasites reveal a unique structural relay mechanism for activation

2019 ◽  
Vol 116 (28) ◽  
pp. 14164-14173 ◽  
Author(s):  
Majida El Bakkouri ◽  
Imène Kouidmi ◽  
Amy K. Wernimont ◽  
Mehrnaz Amani ◽  
Ashley Hutchinson ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Conformational Changes ◽  
Catalytic Domain ◽  
Kinase Domain ◽  
Complex Life Cycle ◽  
Dependent Protein Kinase ◽  
Malaria Parasites ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein ◽  
Developmental Switches

The cyclic guanosine-3′,5′-monophosphate (cGMP)-dependent protein kinase (PKG) was identified >25 y ago; however, efforts to obtain a structure of the entire PKG enzyme or catalytic domain from any species have failed. In malaria parasites, cooperative activation of PKG triggers crucial developmental transitions throughout the complex life cycle. We have determined the cGMP-free crystallographic structures of PKG fromPlasmodium falciparumandPlasmodium vivax, revealing how key structural components, including an N-terminal autoinhibitory segment (AIS), four predicted cyclic nucleotide-binding domains (CNBs), and a kinase domain (KD), are arranged when the enzyme is inactive. The four CNBs and the KD are in a pentagonal configuration, with the AIS docked in the substrate site of the KD in a swapped-domain dimeric arrangement. We show that although the protein is predominantly a monomer (the dimer is unlikely to be representative of the physiological form), the binding of the AIS is necessary to keepPlasmodiumPKG inactive. A major feature is a helix serving the dual role of the N-terminal helix of the KD as well as the capping helix of the neighboring CNB. A network of connecting helices between neighboring CNBs contributes to maintaining the kinase in its inactive conformation. We propose a scheme in which cooperative binding of cGMP, beginning at the CNB closest to the KD, transmits conformational changes around the pentagonal molecule in a structural relay mechanism, enabling PKG to orchestrate rapid, highly regulated developmental switches in response to dynamic modulation of cGMP levels in the parasite.

Stimulation of cGMP-dependent protein kinase (G-kinase) by peptide-546

Neuropeptides ◽  
1994 ◽  
Vol 26 ◽  
pp. 3
Author(s):  
J.P. Huggins ◽  
A.J. Ganzhorn ◽  
V. Saudek ◽  
J.T. Pelton ◽  
R.A. Atkinson
Keyword(s):  
Protein Kinase ◽  
Protein Kinase G ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein ◽  
Stimulation Of

scholarly journals Cardioprotection by H2S engages a cGMP-dependent protein kinase G/phospholamban pathway

2015 ◽  
Vol 106 (3) ◽  
pp. 432-442 ◽  
Author(s):  
Sofia-Iris Bibli ◽  
Ioanna Andreadou ◽  
Athanasia Chatzianastasiou ◽  
Christos Tzimas ◽  
Despina Sanoudou ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase G ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

cDNA Cloning and Gene Expression of Human Type Iα cGMP-Dependent Protein Kinase

Hypertension ◽  
1996 ◽  
Vol 27 (3) ◽  
pp. 552-557 ◽  
Author(s):  
Naohisa Tamura ◽  
Hiroshi Itoh ◽  
Yoshihiro Ogawa ◽  
Osamu Nakagawa ◽  
Masaki Harada ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Cdna Cloning ◽  
Dependent Protein Kinase ◽  
Human Type ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein
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