{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T08:20:29Z","timestamp":1789546829150,"version":"build-2803163510"},"update-to":[{"DOI":"10.1371\/journal.pbio.3001483","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T00:00:00Z","timestamp":1639958400000}}],"reference-count":97,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T00:00:00Z","timestamp":1638921600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"crossref","award":["BSCGI0_157729"],"award-info":[{"award-number":["BSCGI0_157729"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"crossref","award":["310030_156264"],"award-info":[{"award-number":["310030_156264"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Rudolf Geigy Foundation"},{"name":"Horizon 2020 Marie Sk\u0142odowska-Curie Actions","award":["860875"],"award-info":[{"award-number":["860875"]}]},{"name":"Medical Research Council","award":["MR\/N009274\/1"],"award-info":[{"award-number":["MR\/N009274\/1"]}]},{"name":"EPA Cephalosporin Fund","award":["CF 329"],"award-info":[{"award-number":["CF 329"]}]}],"content-domain":{"domain":["www.plosbiology.org"],"crossmark-restriction":false},"short-container-title":["PLoS Biol"],"abstract":"<jats:p>\n                    Cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) signalling is essential for the proliferation of\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    malaria blood stage parasites. The mechanisms regulating the activity of the catalytic subunit PfPKAc, however, are only partially understood, and PfPKAc function has not been investigated in gametocytes, the sexual blood stage forms that are essential for malaria transmission. By studying a conditional PfPKAc knockdown (cKD) mutant, we confirm the essential role for PfPKAc in erythrocyte invasion by merozoites and show that PfPKAc is involved in regulating gametocyte deformability. We furthermore demonstrate that overexpression of PfPKAc is lethal and kills parasites at the early phase of schizogony. Strikingly, whole genome sequencing (WGS) of parasite mutants selected to tolerate increased PfPKAc expression levels identified missense mutations exclusively in the gene encoding the parasite orthologue of 3-phosphoinositide\u2013dependent protein kinase-1 (PfPDK1). Using targeted mutagenesis, we demonstrate that PfPDK1 is required to activate PfPKAc and that T189 in the PfPKAc activation loop is the crucial target residue in this process. In summary, our results corroborate the importance of tight regulation of PfPKA signalling for parasite survival and imply that PfPDK1 acts as a crucial upstream regulator in this pathway and potential new drug target.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3001483","type":"journal-article","created":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T13:45:12Z","timestamp":1638971112000},"page":"e3001483","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":28,"title":["The 3-phosphoinositide\u2013dependent protein kinase 1 is an essential upstream activator of protein kinase A in malaria parasites"],"prefix":"10.1371","volume":"19","author":[{"given":"Eva","family":"Hitz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9470-4284","authenticated-orcid":true,"given":"Natalie","family":"Wiedemar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5970-3339","authenticated-orcid":true,"given":"Armin","family":"Passecker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4497-7107","authenticated-orcid":true,"given":"Beatriz A. S.","family":"Gra\u00e7a","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Scheurer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Wittlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas M. B.","family":"Brancucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4726-0446","authenticated-orcid":true,"given":"Ioannis","family":"Vakonakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3122-1941","authenticated-orcid":true,"given":"Pascal","family":"M\u00e4ser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1464-4988","authenticated-orcid":true,"given":"Till S.","family":"Voss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,12,8]]},"reference":[{"issue":"7491","key":"pbio.3001483.ref001","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1038\/nature12970","article-title":"A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium","volume":"507","author":"A Sinha","year":"2014","journal-title":"Nature"},{"issue":"7491","key":"pbio.3001483.ref002","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nature12920","article-title":"A transcriptional switch underlies commitment to sexual development in malaria parasites","volume":"507","author":"BF Kafsack","year":"2014","journal-title":"Nature"},{"issue":"7","key":"pbio.3001483.ref003","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.1016\/j.cell.2017.10.020","article-title":"Lysophosphatidylcholine Regulates Sexual Stage Differentiation in the Human Malaria Parasite Plasmodium falciparum","volume":"171","author":"NMB Brancucci","year":"2017","journal-title":"Cell"},{"issue":"2","key":"pbio.3001483.ref004","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.chom.2017.07.003","article-title":"The Molecular Basis of Erythrocyte Invasion by Malaria Parasites","volume":"22","author":"AF Cowman","year":"2017","journal-title":"Cell Host Microbe"},{"key":"pbio.3001483.ref005","doi-asserted-by":"crossref","first-page":"34479","DOI":"10.1038\/srep34479","article-title":"Hierarchical phosphorylation of apical membrane antigen 1 is required for efficient red blood cell invasion by malaria parasites","volume":"6","author":"B Prinz","year":"2016","journal-title":"Sci Rep"},{"issue":"6","key":"pbio.3001483.ref006","doi-asserted-by":"crossref","first-page":"e1000941","DOI":"10.1371\/journal.ppat.1000941","article-title":"Protein kinase a dependent phosphorylation of apical membrane antigen 1 plays an important role in erythrocyte invasion by the malaria parasite","volume":"6","author":"K Leykauf","year":"2010","journal-title":"PLoS Pathog"},{"issue":"3","key":"pbio.3001483.ref007","doi-asserted-by":"crossref","first-page":"e1000322","DOI":"10.1371\/journal.ppat.1000322","article-title":"Functional analysis of the leading malaria vaccine candidate AMA-1 reveals an essential role for the cytoplasmic domain in the invasion process","volume":"5","author":"M Treeck","year":"2009","journal-title":"PLoS Pathog."},{"issue":"5","key":"pbio.3001483.ref008","doi-asserted-by":"crossref","first-page":"e3000264","DOI":"10.1371\/journal.pbio.3000264","article-title":"Cyclic AMP signalling controls key components of malaria parasite host cell invasion machinery","volume":"17","author":"A Patel","year":"2019","journal-title":"PLoS Biol"},{"issue":"5","key":"pbio.3001483.ref009","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.01972-19","article-title":"Protein Kinase A Is Essential for Invasion of Plasmodium falciparum into Human Erythrocytes","volume":"10","author":"ML Wilde","year":"2019","journal-title":"MBio"},{"issue":"13","key":"pbio.3001483.ref010","doi-asserted-by":"crossref","first-page":"3763","DOI":"10.1016\/S0021-9258(19)34204-8","article-title":"An adenosine 3\u2019,5\u2019-monophosphate-dependant protein kinase from rabbit skeletal muscle","volume":"243","author":"DA Walsh","year":"1968","journal-title":"J Biol Chem"},{"issue":"7","key":"pbio.3001483.ref011","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1016\/j.bbapap.2013.03.007","article-title":"PKA: lessons learned after twenty years","volume":"1834","author":"SS Taylor","year":"2013","journal-title":"Biochim Biophys Acta"},{"issue":"49","key":"pbio.3001483.ref012","doi-asserted-by":"crossref","first-page":"47878","DOI":"10.1074\/jbc.M204970200","article-title":"Phosphorylation of the catalytic subunit of protein kinase A. Autophosphorylation versus phosphorylation by phosphoinositide-dependent kinase-1","volume":"277","author":"MJ Moore","year":"2002","journal-title":"J Biol Chem"},{"issue":"8","key":"pbio.3001483.ref013","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1093\/protein\/10.8.915","article-title":"Autophosphorylation of the catalytic subunit of cAMP-dependent protein kinase in Escherichia coli","volume":"10","author":"W Yonemoto","year":"1997","journal-title":"Protein Eng"},{"issue":"25","key":"pbio.3001483.ref014","doi-asserted-by":"crossref","first-page":"22017","DOI":"10.1074\/jbc.M110.200071","article-title":"Yeast 3-phosphoinositide-dependent protein kinase-1 (PDK1) orthologs Pkh1-3 differentially regulate phosphorylation of protein kinase A (PKA) and the protein kinase B (PKB)\/S6K ortholog Sch9","volume":"286","author":"K Voordeckers","year":"2011","journal-title":"J Biol Chem"},{"issue":"3","key":"pbio.3001483.ref015","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1128\/MCB.18.3.1416","article-title":"Physiological phosphorylation of protein kinase A at Thr-197 is by a protein kinase A kinase","volume":"18","author":"RD Cauthron","year":"1998","journal-title":"Mol Cell Biol"},{"issue":"7","key":"pbio.3001483.ref016","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1084\/jem.20051715","article-title":"Phosphoinositide-dependent kinase 1 targets protein kinase A in a pathway that regulates interleukin 4","volume":"203","author":"A Nirula","year":"2006","journal-title":"J Exp Med"},{"key":"pbio.3001483.ref017","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.semcancer.2017.05.011","article-title":"AGC kinases, mechanisms of regulation and innovative drug development","volume":"48","author":"AE Leroux","year":"2018","journal-title":"Semin Cancer Biol"},{"issue":"4","key":"pbio.3001483.ref018","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1534\/genetics.104.032466","article-title":"In vivo activation of protein kinase A in Schizosaccharomyces pombe requires threonine phosphorylation at its activation loop and is dependent on PDK1","volume":"168","author":"Y Tang","year":"2004","journal-title":"Genetics"},{"issue":"4","key":"pbio.3001483.ref019","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/S0960-9822(06)00122-9","article-title":"Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha","volume":"7","author":"DR Alessi","year":"1997","journal-title":"Curr Biol"},{"issue":"5325","key":"pbio.3001483.ref020","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1126\/science.277.5325.567","article-title":"Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B","volume":"277","author":"D Stokoe","year":"1997","journal-title":"Science"},{"issue":"2","key":"pbio.3001483.ref021","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.semcdb.2003.12.022","article-title":"PDK1, the master regulator of AGC kinase signal transduction","volume":"15","author":"A Mora","year":"2004","journal-title":"Semin Cell Dev Biol"},{"issue":"5","key":"pbio.3001483.ref022","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1093\/emboj\/19.5.979","article-title":"Identification of a pocket in the PDK1 kinase domain that interacts with PIF and the C-terminal residues of PKA","volume":"19","author":"RM Biondi","year":"2000","journal-title":"EMBO J"},{"issue":"17","key":"pbio.3001483.ref023","doi-asserted-by":"crossref","first-page":"9849","DOI":"10.1073\/pnas.95.17.9849","article-title":"Phosphorylation and activation of cAMP-dependent protein kinase by phosphoinositide-dependent protein kinase","volume":"95","author":"X Cheng","year":"1998","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6","key":"pbio.3001483.ref024","doi-asserted-by":"crossref","first-page":"3825","DOI":"10.1074\/jbc.M109.061820","article-title":"Global consequences of activation loop phosphorylation on protein kinase A","volume":"285","author":"JM Steichen","year":"2010","journal-title":"J Biol Chem"},{"issue":"2","key":"pbio.3001483.ref025","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/S0166-6851(00)00242-5","article-title":"Isolation and characterisation of a cAMP-dependent protein kinase catalytic subunit gene from Plasmodium falciparum","volume":"109","author":"J Li","year":"2000","journal-title":"Mol Biochem Parasitol"},{"issue":"12","key":"pbio.3001483.ref026","doi-asserted-by":"crossref","DOI":"10.1098\/rsob.170213","article-title":"Cyclic nucleotide signalling in malaria parasites","volume":"7","author":"DA Baker","year":"2017","journal-title":"Open Biol."},{"issue":"2","key":"pbio.3001483.ref027","doi-asserted-by":"crossref","first-page":"e3000154","DOI":"10.1371\/journal.pbio.3000154","article-title":"Phosphodiesterase beta is the master regulator of cAMP signalling during malaria parasite invasion","volume":"17","author":"C Flueck","year":"2019","journal-title":"PLoS Biol"},{"issue":"2","key":"pbio.3001483.ref028","doi-asserted-by":"crossref","first-page":"e19","DOI":"10.1371\/journal.ppat.0040019","article-title":"Plasmodium falciparum regulatory subunit of cAMP-dependent PKA and anion channel conductance","volume":"4","author":"A Merckx","year":"2008","journal-title":"PLoS Pathog"},{"issue":"1","key":"pbio.3001483.ref029","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1038\/s42003-020-01454-7","article-title":"Plasmodium falciparum sexual parasites regulate infected erythrocyte permeability","volume":"3","author":"G Bouyer","year":"2020","journal-title":"Commun Biol"},{"issue":"5","key":"pbio.3001483.ref030","doi-asserted-by":"crossref","first-page":"e1004815","DOI":"10.1371\/journal.ppat.1004815","article-title":"cAMP-Signalling Regulates Gametocyte-Infected Erythrocyte Deformability Required for Malaria Parasite Transmission","volume":"11","author":"G Ramdani","year":"2015","journal-title":"PLoS Pathog"},{"key":"pbio.3001483.ref031","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/ncomms1558","article-title":"Global kinomic and phospho-proteomic analyses of the human malaria parasite Plasmodium falciparum","volume":"2","author":"L Solyakov","year":"2011","journal-title":"Nat Commun"},{"issue":"15","key":"pbio.3001483.ref032","doi-asserted-by":"crossref","first-page":"2716","DOI":"10.1002\/pmic.201400508","article-title":"Extensive differential protein phosphorylation as intraerythrocytic Plasmodium falciparum schizonts develop into extracellular invasive merozoites","volume":"15","author":"E Lasonder","year":"2015","journal-title":"Proteomics"},{"issue":"11","key":"pbio.3001483.ref033","doi-asserted-by":"crossref","first-page":"5323","DOI":"10.1021\/pr300557m","article-title":"The Plasmodium falciparum schizont phosphoproteome reveals extensive phosphatidylinositol and cAMP-protein kinase A signaling","volume":"11","author":"E Lasonder","year":"2012","journal-title":"J Proteome Res"},{"issue":"4","key":"pbio.3001483.ref034","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.chom.2011.09.004","article-title":"The phosphoproteomes of Plasmodium falciparum and Toxoplasma gondii reveal unusual adaptations within and beyond the parasites\u2019 boundaries","volume":"10","author":"M Treeck","year":"2011","journal-title":"Cell Host Microbe"},{"issue":"4","key":"pbio.3001483.ref035","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/nmeth.4223","article-title":"A genetic system to study Plasmodium falciparum protein function","volume":"14","author":"J Birnbaum","year":"2017","journal-title":"Nat Methods"},{"issue":"12","key":"pbio.3001483.ref036","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1038\/nmeth1132","article-title":"An FKBP destabilization domain modulates protein levels in Plasmodium falciparum","volume":"4","author":"CM Armstrong","year":"2007","journal-title":"Nat Methods"},{"issue":"5","key":"pbio.3001483.ref037","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/j.cell.2006.07.025","article-title":"A rapid, reversible, and tunable method to regulate protein function in living cells using synthetic small molecules","volume":"126","author":"LA Banaszynski","year":"2006","journal-title":"Cell"},{"issue":"10","key":"pbio.3001483.ref038","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1038\/nmeth.2143","article-title":"Site-specific genome editing in Plasmodium falciparum using engineered zinc-finger nucleases","volume":"9","author":"J Straimer","year":"2012","journal-title":"Nat Methods"},{"issue":"5","key":"pbio.3001483.ref039","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1038\/nbt957","article-title":"Correction of multi-gene deficiency in vivo using a single \u2019self-cleaving\u2019 2A peptide-based retroviral vector","volume":"22","author":"AL Szymczak","year":"2004","journal-title":"Nat Biotechnol"},{"issue":"8","key":"pbio.3001483.ref040","doi-asserted-by":"crossref","first-page":"e73783","DOI":"10.1371\/journal.pone.0073783","article-title":"Inducible knockdown of Plasmodium gene expression using the glmS ribozyme","volume":"8","author":"P Prommana","year":"2013","journal-title":"PLoS ONE"},{"key":"pbio.3001483.ref041","article-title":"Revisiting the effect of pharmaceuticals on transmission stage formation in the malaria parasite Plasmodium falciparum","author":"BT Thommen","year":"2021","journal-title":"BioRxiv [Preprint"},{"key":"pbio.3001483.ref042","doi-asserted-by":"crossref","first-page":"70","DOI":"10.12688\/wellcomeopenres.14645.4","article-title":"Probing Plasmodium falciparum sexual commitment at the single-cell level","volume":"3","author":"NMB Brancucci","year":"2018","journal-title":"Wellcome Open Res"},{"issue":"5","key":"pbio.3001483.ref043","doi-asserted-by":"crossref","first-page":"102444","DOI":"10.1016\/j.isci.2021.102444","article-title":"The ApiAP2 factor PfAP2-HC is an integral component of heterochromatin in the malaria parasite Plasmodium falciparum","volume":"24","author":"E Carrington","year":"2021","journal-title":"iScience"},{"issue":"1","key":"pbio.3001483.ref044","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.molbiopara.2007.04.008","article-title":"Improved synchronous production of Plasmodium falciparum gametocytes in vitro","volume":"154","author":"QL Fivelman","year":"2007","journal-title":"Mol Biochem Parasitol"},{"issue":"17","key":"pbio.3001483.ref045","doi-asserted-by":"crossref","first-page":"4800","DOI":"10.1073\/pnas.1520194113","article-title":"Reversible host cell remodeling underpins deformability changes in malaria parasite sexual blood stages","volume":"113","author":"M Dearnley","year":"2016","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pbio.3001483.ref046","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/978-1-62703-026-7_20","article-title":"Microsphiltration: a microsphere matrix to explore erythrocyte deformability","volume":"923","author":"C Lavazec","year":"2013","journal-title":"Methods Mol Biol"},{"issue":"24","key":"pbio.3001483.ref047","doi-asserted-by":"crossref","first-page":"e172","DOI":"10.1182\/blood-2012-03-414557","article-title":"A switch in infected erythrocyte deformability at the maturation and blood circulation of Plasmodium falciparum transmission stages","volume":"119","author":"M Tiburcio","year":"2012","journal-title":"Blood"},{"issue":"8","key":"pbio.3001483.ref048","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1038\/nmeth904","article-title":"Efficient site-specific integration in Plasmodium falciparum chromosomes mediated by mycobacteriophage Bxb1 integrase","volume":"3","author":"LJ Nkrumah","year":"2006","journal-title":"Nat Methods"},{"issue":"6","key":"pbio.3001483.ref049","doi-asserted-by":"crossref","first-page":"e0157873","DOI":"10.1371\/journal.pone.0157873","article-title":"Development and Application of a Simple Plaque Assay for the Human Malaria Parasite Plasmodium falciparum","volume":"11","author":"JA Thomas","year":"2016","journal-title":"PLoS ONE"},{"issue":"6","key":"pbio.3001483.ref050","doi-asserted-by":"crossref","first-page":"642","DOI":"10.4161\/psb.20038","article-title":"Perspectives in PDK1 evolution: insights from photosynthetic and non-photosynthetic organisms","volume":"7","author":"AC Dittrich","year":"2012","journal-title":"Plant Signal Behav"},{"issue":"20","key":"pbio.3001483.ref051","doi-asserted-by":"crossref","first-page":"3918","DOI":"10.1038\/sj.emboj.7600379","article-title":"Structural insights into the regulation of PDK1 by phosphoinositides and inositol phosphates","volume":"23","author":"D Komander","year":"2004","journal-title":"EMBO J"},{"issue":"2","key":"pbio.3001483.ref052","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.str.2004.01.005","article-title":"Interactions of LY333531 and other bisindolyl maleimide inhibitors with PDK1","volume":"12","author":"D Komander","year":"2004","journal-title":"Structure"},{"issue":"6381","key":"pbio.3001483.ref053","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1126\/science.aan6042","article-title":"GDV1 induces sexual commitment of malaria parasites by antagonizing HP1-dependent gene silencing","volume":"359","author":"M Filarsky","year":"2018","journal-title":"Science"},{"issue":"6388","key":"pbio.3001483.ref054","doi-asserted-by":"crossref","DOI":"10.1126\/science.aap7847","article-title":"Uncovering the essential genes of the human malaria parasite Plasmodium falciparum by saturation mutagenesis","volume":"360","author":"M Zhang","year":"2018","journal-title":"Science"},{"issue":"4","key":"pbio.3001483.ref055","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.chom.2010.09.006","article-title":"The systematic functional analysis of Plasmodium protein kinases identifies essential regulators of mosquito transmission","volume":"8","author":"R Tewari","year":"2010","journal-title":"Cell Host Microbe"},{"issue":"4","key":"pbio.3001483.ref056","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1016\/j.chom.2018.03.007","article-title":"Chromatin Accessibility-Based Characterization of the Gene Regulatory Network Underlying Plasmodium falciparum Blood-Stage Development","volume":"23","author":"CG Toenhake","year":"2018","journal-title":"Cell Host Microbe"},{"issue":"5","key":"pbio.3001483.ref057","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1101\/gr.129692.111","article-title":"Transcriptional variation in the malaria parasite Plasmodium falciparum","volume":"22","author":"N Rovira-Graells","year":"2012","journal-title":"Genome Res"},{"issue":"5","key":"pbio.3001483.ref058","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1091\/mbc.e12-09-0677","article-title":"Mapping and analysis of phosphorylation sites: a quick guide for cell biologists","volume":"24","author":"N Dephoure","year":"2013","journal-title":"Mol Biol Cell"},{"issue":"44","key":"pbio.3001483.ref059","doi-asserted-by":"crossref","first-page":"27715","DOI":"10.1016\/S0021-9258(18)47044-5","article-title":"Requirement for negative charge on \"activation loop\" of protein kinase C","volume":"269","author":"JW Orr","year":"1994","journal-title":"J Biol Chem"},{"key":"pbio.3001483.ref060","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.semcancer.2017.04.014","article-title":"PDK1: At the crossroad of cancer signaling pathways","volume":"48","author":"PA Gagliardi","year":"2018","journal-title":"Semin Cancer Biol"},{"issue":"5","key":"pbio.3001483.ref061","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1517\/13543776.2015.1014801","article-title":"PDK1 disruptors and modulators: a patent review","volume":"25","author":"MJ Hossen","year":"2015","journal-title":"Expert Opin Ther Pat"},{"issue":"4","key":"pbio.3001483.ref062","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1080\/13543776.2019.1597852","article-title":"A patent update on PDK1 inhibitors (2015-present)","volume":"29","author":"S Sestito","year":"2019","journal-title":"Expert Opin Ther Pat"},{"issue":"7","key":"pbio.3001483.ref063","doi-asserted-by":"crossref","first-page":"2726","DOI":"10.1021\/jm4000227","article-title":"Selective 3-phosphoinositide-dependent kinase 1 (PDK1) inhibitors: dissecting the function and pharmacology of PDK1","volume":"56","author":"JR Medina","year":"2013","journal-title":"J Med Chem"},{"issue":"20","key":"pbio.3001483.ref064","doi-asserted-by":"crossref","first-page":"19867","DOI":"10.1074\/jbc.M501367200","article-title":"Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1","volume":"280","author":"RI Feldman","year":"2005","journal-title":"J Biol Chem"},{"issue":"2","key":"pbio.3001483.ref065","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1042\/BJ20101732","article-title":"Characterization of GSK2334470, a novel and highly specific inhibitor of PDK1","volume":"433","author":"A Najafov","year":"2011","journal-title":"Biochem J"},{"issue":"6","key":"pbio.3001483.ref066","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1021\/jm101527u","article-title":"Structure-based design of potent and selective 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitors","volume":"54","author":"JR Medina","year":"2011","journal-title":"J Med Chem"},{"issue":"3","key":"pbio.3001483.ref067","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1042\/BJ20070797","article-title":"The selectivity of protein kinase inhibitors: a further update","volume":"408","author":"J Bain","year":"2007","journal-title":"Biochem J"},{"issue":"3","key":"pbio.3001483.ref068","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.exppara.2006.09.016","article-title":"In vitro and in vivo interaction of synthetic peroxide RBx11160 (OZ277) with piperaquine in Plasmodium models","volume":"115","author":"C Snyder","year":"2007","journal-title":"Exp Parasitol"},{"issue":"5772","key":"pbio.3001483.ref069","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1038\/286490a0","article-title":"Gametocytogenesis by malaria parasites in continuous culture","volume":"286","author":"DC Kaushal","year":"1980","journal-title":"Nature"},{"issue":"3","key":"pbio.3001483.ref070","doi-asserted-by":"crossref","first-page":"346","DOI":"10.2307\/3283117","article-title":"Comparison of adenylate cyclase and cAMP-dependent protein kinase in gametocytogenic and nongametocytogenic clones of Plasmodium falciparum","volume":"77","author":"LK Read","year":"1991","journal-title":"J Parasitol"},{"issue":"21","key":"pbio.3001483.ref071","doi-asserted-by":"crossref","first-page":"e131","DOI":"10.1093\/nar\/gng131","article-title":"Regulation of Cre recombinase by ligand-induced complementation of inactive fragments","volume":"31","author":"N Jullien","year":"2003","journal-title":"Nucleic Acids Res"},{"key":"pbio.3001483.ref072","doi-asserted-by":"crossref","first-page":"21800","DOI":"10.1038\/srep21800","article-title":"A versatile strategy for rapid conditional genome engineering using loxP sites in a small synthetic intron in Plasmodium falciparum","volume":"6","author":"ML Jones","year":"2016","journal-title":"Sci Rep"},{"issue":"4","key":"pbio.3001483.ref073","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1111\/mmi.12206","article-title":"Robust inducible Cre recombinase activity in the human malaria parasite Plasmodium falciparum enables efficient gene deletion within a single asexual erythrocytic growth cycle","volume":"88","author":"CR Collins","year":"2013","journal-title":"Mol Microbiol"},{"issue":"24","key":"pbio.3001483.ref074","doi-asserted-by":"crossref","first-page":"e42","DOI":"10.1182\/blood-2016-01-690776","article-title":"Plasmodium falciparum STEVOR phosphorylation regulates host erythrocyte deformability enabling malaria parasite transmission","volume":"127","author":"B Naissant","year":"2016","journal-title":"Blood"},{"issue":"Pt 8","key":"pbio.3001483.ref075","first-page":"2053","article-title":"Origin, composition, organization and function of the inner membrane complex of Plasmodium falciparum gametocytes","volume":"125","author":"MK Dearnley","year":"2012","journal-title":"J Cell Sci"},{"issue":"9","key":"pbio.3001483.ref076","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1093\/molbev\/mss081","article-title":"Evolution and architecture of the inner membrane complex in asexual and sexual stages of the malaria parasite","volume":"29","author":"M Kono","year":"2012","journal-title":"Mol Biol Evol"},{"issue":"10","key":"pbio.3001483.ref077","doi-asserted-by":"crossref","first-page":"e1006659","DOI":"10.1371\/journal.ppat.1006659","article-title":"Disrupting assembly of the inner membrane complex blocks Plasmodium falciparum sexual stage development","volume":"13","author":"M Parkyn Schneider","year":"2017","journal-title":"PLoS Pathog"},{"key":"pbio.3001483.ref078","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.mib.2020.09.003","article-title":"cAMP signalling and its role in host cell invasion by malaria parasites","volume":"58","author":"AJ Perrin","year":"2020","journal-title":"Curr Opin Microbiol"},{"issue":"1","key":"pbio.3001483.ref079","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1128\/EC.00186-09","article-title":"The malaria parasite cyclic GMP-dependent protein kinase plays a central role in blood-stage schizogony","volume":"9","author":"HM Taylor","year":"2010","journal-title":"Eukaryot Cell"},{"issue":"3","key":"pbio.3001483.ref080","doi-asserted-by":"crossref","first-page":"418","DOI":"10.2307\/3280287","article-title":"Synchronization of Plasmodium falciparum erythrocytic stages in culture","volume":"65","author":"C Lambros","year":"1979","journal-title":"J Parasitol"},{"issue":"4","key":"pbio.3001483.ref081","doi-asserted-by":"crossref","first-page":"743","DOI":"10.4269\/ajtmh.1978.27.743","article-title":"Plasmodium falciparum in culture: establishment of additional strains","volume":"27","author":"JB Jensen","year":"1978","journal-title":"Am J Trop Med Hyg"},{"issue":"1","key":"pbio.3001483.ref082","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1038\/s42003-021-01873-0","article-title":"The catalytic subunit of Plasmodium falciparum casein kinase 2 is essential for gametocytogenesis","volume":"4","author":"E Hitz","year":"2021","journal-title":"Commun Biol"},{"issue":"8","key":"pbio.3001483.ref083","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1038\/nbt.2925","article-title":"Genome editing in the human malaria parasite Plasmodium falciparum using the CRISPR-Cas9 system","volume":"32","author":"M Ghorbal","year":"2014","journal-title":"Nat Biotechnol"},{"issue":"1","key":"pbio.3001483.ref084","doi-asserted-by":"crossref","first-page":"4806","DOI":"10.1038\/s41467-021-24954-4","article-title":"CRISPR\/Cas9-engineered inducible gametocyte producer lines as a valuable tool for Plasmodium falciparum malaria transmission research","volume":"12","author":"SD Boltryk","year":"2021","journal-title":"Nat Commun"},{"issue":"2","key":"pbio.3001483.ref085","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1111\/j.1365-2958.2012.08019.x","article-title":"Analysis of subtelomeric virulence gene families in Plasmodium falciparum by comparative transcriptional profiling","volume":"84","author":"K Witmer","year":"2012","journal-title":"Mol Microbiol"},{"issue":"8","key":"pbio.3001483.ref086","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1515\/BC.2003.135","article-title":"The N\u2019-terminal domain of glyceraldehyde-3-phosphate dehydrogenase of the apicomplexan Plasmodium falciparum mediates GTPase Rab2-dependent recruitment to membranes","volume":"384","author":"CA Daubenberger","year":"2003","journal-title":"Biol Chem"},{"issue":"9","key":"pbio.3001483.ref087","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1038\/nprot.2016.096","article-title":"Routine in vitro culture of P. falciparum gametocytes to evaluate novel transmission-blocking interventions","volume":"11","author":"MJ Delves","year":"2016","journal-title":"Nat Protoc"},{"key":"pbio.3001483.ref088","first-page":"159","article-title":"Extraction and purification of Plasmodium parasite DNA","volume":"72","author":"HP Beck","year":"2002","journal-title":"Methods Mol Med"},{"key":"pbio.3001483.ref089","author":"Babraham-Bioinformatics","year":"2017","journal-title":"FastQC A Quality Control tool for High Throughput Sequence Data"},{"issue":"14","key":"pbio.3001483.ref090","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows-Wheeler transform","volume":"25","author":"H Li","year":"2009","journal-title":"Bioinformatics"},{"issue":"16","key":"pbio.3001483.ref091","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The Sequence Alignment\/Map format and SAMtools","volume":"25","author":"H Li","year":"2009","journal-title":"Bioinformatics"},{"key":"pbio.3001483.ref092","author":"Broad_Institute","year":"2017","journal-title":"Picard Tools"},{"issue":"9","key":"pbio.3001483.ref093","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"A McKenna","year":"2010","journal-title":"Genome Res"},{"issue":"2","key":"pbio.3001483.ref094","doi-asserted-by":"crossref","first-page":"80","DOI":"10.4161\/fly.19695","article-title":"A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3","volume":"6","author":"P Cingolani","year":"2012","journal-title":"Fly (Austin)"},{"issue":"2","key":"pbio.3001483.ref095","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1093\/bib\/bbs017","article-title":"Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration","volume":"14","author":"H Thorvaldsdottir","year":"2013","journal-title":"Brief Bioinform"},{"issue":"W1","key":"pbio.3001483.ref096","doi-asserted-by":"crossref","first-page":"W636","DOI":"10.1093\/nar\/gkz268","article-title":"The EMBL-EBI search and sequence analysis tools APIs in 2019","volume":"47","author":"F Madeira","year":"2019","journal-title":"Nucleic Acids Res"},{"issue":"W1","key":"pbio.3001483.ref097","doi-asserted-by":"crossref","first-page":"W296","DOI":"10.1093\/nar\/gky427","article-title":"SWISS-MODEL: homology modelling of protein structures and complexes","volume":"46","author":"A Waterhouse","year":"2018","journal-title":"Nucleic Acids Res"}],"updated-by":[{"DOI":"10.1371\/journal.pbio.3001483","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T00:00:00Z","timestamp":1639958400000}}],"container-title":["PLOS Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pbio.3001483","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T14:12:29Z","timestamp":1640009549000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pbio.3001483"}},"subtitle":[],"editor":[{"given":"Boris","family":"Striepen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,12,8]]},"references-count":97,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12,8]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pbio.3001483","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.05.27.445967","asserted-by":"object"}]},"ISSN":["1545-7885"],"issn-type":[{"value":"1545-7885","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,8]]}}}