5e16
Co-crystal structure of the N-termial cGMP binding domain of Plasmodium falciparum PKG with cGMP
Structural highlights
FunctionKGP_PLAF7 Serine/threonine protein kinase which acts as a downstream effector of the second messenger cGMP (PubMed:12068803, PubMed:12817987, PubMed:26149123). Controls the release of Ca(2+) from intracellular stores by regulating phosphoinositide biosynthesis (PubMed:24594931). Ca(2+) signals are essential for merozoite and sporozoite invasion and egress from host hepatocytes and erythrocytes, and, in the mosquito vector, for gametocyte activation, and ookinete and sporozoite motility (PubMed:24594931). During the host liver stage, regulates the initial invasion of host hepatocytes by sporozoites by regulating sporozoite motility and microneme exocytosis (By similarity). Following parasite development in the hepatocytes, required for the release of merosomes, a vesicle containing the mature merozoites (By similarity). During the asexual blood stage, required for the progression from schizont to the ring stage following merozoite invasion of host erythrocytes and for merozoite egress (PubMed:19915077, PubMed:26149123, PubMed:25646845). Regulates merozoite egress by promoting the release of exonemes and micronemes which contain proteins essential for egress (PubMed:23675297). Phosphorylates CDPK1 predominantly at the late schizont stage; phosphorylation at 'Ser-64' regulates CDPK1 protein-protein interaction and phosphorylation at 'Thr-231' may regulate CDPK1 kinase activity (PubMed:26149123). Phosphorylates MyoA at 'Ser-19' (PubMed:26149123). In the mosquito vector, required for the initiation of gametogenesis induced by xanthurenic acid, specifically the gametocyte differentiation from the crescent-shaped form to the spherical form (PubMed:18532880). Required for the gliding motility of ookinetes to reach and penetrate the midgut epithelium by promoting Ca(2+)-mediated activation of CDPK1 and CDPK4 (By similarity). Also required for microneme secretion in ookinete by promoting Ca(2+)-mediated activation of CDPK3 (By similarity).[UniProtKB:A0A509AKL0][1] [2] [3] [4] [5] [6] [7] [8] Publication Abstract from PubMedThe 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 from Plasmodium falciparum and Plasmodium 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 keep Plasmodium PKG 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. Structures of the cGMP-dependent protein kinase in malaria parasites reveal a unique structural relay mechanism for activation.,El Bakkouri M, Kouidmi I, Wernimont AK, Amani M, Hutchinson A, Loppnau P, Kim JJ, Flueck C, Walker JR, Seitova A, Senisterra G, Kakihara Y, Kim C, Blackman MJ, Calmettes C, Baker DA, Hui R Proc Natl Acad Sci U S A. 2019 Jul 9;116(28):14164-14173. doi:, 10.1073/pnas.1905558116. Epub 2019 Jun 25. PMID:31239348[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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