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.
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 b...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-02-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1004639 |
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| author | Jeong Joo Kim Christian Flueck Eugen Franz Eduardo Sanabria-Figueroa Eloise Thompson Robin Lorenz Daniela Bertinetti David A Baker Friedrich W Herberg Choel Kim |
| author_facet | Jeong Joo Kim Christian Flueck Eugen Franz Eduardo Sanabria-Figueroa Eloise Thompson Robin Lorenz Daniela Bertinetti David A Baker Friedrich W Herberg Choel Kim |
| author_sort | Jeong Joo Kim |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-cdf948dfee564831ba47e158adaa23ca |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2015-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-cdf948dfee564831ba47e158adaa23ca2025-08-20T03:46:13ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742015-02-01112e100463910.1371/journal.ppat.1004639Crystal structures of the carboxyl cGMP binding domain of the Plasmodium falciparum cGMP-dependent protein kinase reveal a novel capping triad crucial for merozoite egress.Jeong Joo KimChristian FlueckEugen FranzEduardo Sanabria-FigueroaEloise ThompsonRobin LorenzDaniela BertinettiDavid A BakerFriedrich W HerbergChoel KimThe 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.https://doi.org/10.1371/journal.ppat.1004639 |
| spellingShingle | Jeong Joo Kim Christian Flueck Eugen Franz Eduardo Sanabria-Figueroa Eloise Thompson Robin Lorenz Daniela Bertinetti David A Baker Friedrich W Herberg Choel Kim 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. PLoS Pathogens |
| 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. |
| title_full | 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. |
| title_fullStr | 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. |
| title_full_unstemmed | 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. |
| title_short | 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. |
| title_sort | 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 |
| url | https://doi.org/10.1371/journal.ppat.1004639 |
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