Crystal Structures of the Carboxyl cGMP Binding Domain of the Plasmodium falciparum cGMP-dependent Protein Kinase Reveal a Novel Capping Triad Crucial for Merozoite Egress

Kim, Jeong Joo; Flueck, Christian; Franz, Eugen; Sanabria-Figueroa, Eduardo; Thompson, Eloise; Lorenz, Robin; Bertinetti, Daniela; Baker, David A.; Herberg, Friedrich W.; Kim, Choel; Soldati-Favre, Dominique

doi:10.1371/journal.ppat.1004639

Title: Crystal Structures of the Carboxyl cGMP Binding Domain of the Plasmodium falciparum cGMP-dependent Protein Kinase Reveal a Novel Capping Triad Crucial for Merozoite Egress

Journal Article · Tue Feb 03 00:00:00 EST 2015 · PLoS Pathogens

DOI:https://doi.org/10.1371/journal.ppat.1004639· OSTI ID:1234756

Kim, Jeong Joo ^[1]; Flueck, Christian ^[2]; Franz, Eugen ^[3]; Sanabria-Figueroa, Eduardo ^[4]; Thompson, Eloise ^[2]; Lorenz, Robin ^[3]; Bertinetti, Daniela ^[3]; Baker, David A. ^[2]; Herberg, Friedrich W. ^[3]; Kim, Choel ^[5]; Soldati-Favre, Dominique ^[6]

Baylor College of Medicine, Houston, TX (United States); Univ. of Kassel, Hesse (Germany)
London School of Hygiene & Tropical Medicine, London (United Kingdom)
Univ. of Kassel, Hesse (Germany)
Emory Univ., Atlanta, GA (United States); Baylor College of Medicine, Houston, TX (United States)
Baylor College of Medicine, Houston, TX (United States)
Univ. of Geneva (Switzerland)

The Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) is a key regulator across the malaria parasite life cycle. Little is known about PfPKG’s activation mechanism. Here we report that the carboxyl cyclic nucleotide binding domain functions as a “gatekeeper” for activation by providing the highest cGMP affinity and selectivity. To understand the mechanism, we have solved its crystal structures with and without cGMP at 2.0 and 1.9 Å, respectively. These structures revealed a PfPKG-specific capping triad that forms upon cGMP binding, and disrupting the triad reduces kinase activity by 90%. Furthermore, mutating these residues in the parasite prevents blood stage merozoite egress, confirming the essential nature of the triad in the parasite. We propose a mechanism of activation where cGMP binding allosterically triggers the conformational change at the αC-helix, which bridges the regulatory and catalytic domains, causing the capping triad to form and stabilize the active conformation.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: Wellcome Trust; National Institutes of Health (NIH)

Grant/Contract Number:: 241481; R01 GM090161; R21 HL111953

OSTI ID:: 1234756

Journal Information:: PLoS Pathogens, Vol. 11, Issue 2; ISSN 1553-7374

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 21 works

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Structures of the cGMP-dependent protein kinase in malaria parasites reveal a unique structural relay mechanism for activation. Bakkouri, Majida El; Kouidmi, Imène; Wernimont, Amy K. The Francis Crick Institute https://doi.org/10.25418/crick.11558427.v1	text	January 2020
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59 BASIC BIOLOGICAL SCIENCES
crystal structure
parasitic life cycles
malarial parasites
plasmodium
blood
merozoites
hydrogen bonding
red blood cells

Title: Crystal Structures of the Carboxyl cGMP Binding Domain of the Plasmodium falciparum cGMP-dependent Protein Kinase Reveal a Novel Capping Triad Crucial for Merozoite Egress

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