Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.ppat.1002553
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dc.titleA P-loop mutation in G? subunits prevents transition to the active state: Implications for G-protein signaling in fungal pathogenesis
dc.contributor.authorBosch D.E.
dc.contributor.authorWillard F.S.
dc.contributor.authorRamanujam R.
dc.contributor.authorKimple A.J.
dc.contributor.authorWillard M.D.
dc.contributor.authorNaqvi N.I.
dc.contributor.authorSiderovski D.P.
dc.date.accessioned2019-11-06T09:30:26Z
dc.date.available2019-11-06T09:30:26Z
dc.date.issued2012
dc.identifier.citationBosch D.E., Willard F.S., Ramanujam R., Kimple A.J., Willard M.D., Naqvi N.I., Siderovski D.P. (2012). A P-loop mutation in G? subunits prevents transition to the active state: Implications for G-protein signaling in fungal pathogenesis. PLoS Pathogens 8 (2) : e1002553. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.ppat.1002553
dc.identifier.issn15537366
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/161643
dc.description.abstractHeterotrimeric G-proteins are molecular switches integral to a panoply of different physiological responses that many organisms make to environmental cues. The switch from inactive to active G??? heterotrimer relies on nucleotide cycling by the G? subunit: exchange of GTP for GDP activates G?, whereas its intrinsic enzymatic activity catalyzes GTP hydrolysis to GDP and inorganic phosphate, thereby reverting G? to its inactive state. In several genetic studies of filamentous fungi, such as the rice blast fungus Magnaporthe oryzae, a G42R mutation in the phosphate-binding loop of G? subunits is assumed to be GTPase-deficient and thus constitutively active. Here, we demonstrate that G?(G42R) mutants are not GTPase deficient, but rather incapable of achieving the activated conformation. Two crystal structure models suggest that Arg-42 prevents a typical switch region conformational change upon G?i1(G42R) binding to GDP·AlF4- or GTP, but rotameric flexibility at this locus allows for unperturbed GTP hydrolysis. G?(G42R) mutants do not engage the active state-selective peptide KB-1753 nor RGS domains with high affinity, but instead favor interaction with G?? and GoLoco motifs in any nucleotide state. The corresponding G?q(G48R) mutant is not constitutively active in cells and responds poorly to aluminum tetrafluoride activation. Comparative analyses of M. oryzae strains harboring either G42R or GTPase-deficient Q/L mutations in the G? subunits MagA or MagB illustrate functional differences in environmental cue processing and intracellular signaling outcomes between these two G? mutants, thus demonstrating the in vivo functional divergence of G42R and activating G-protein mutants. © 2012 Bosch et al.
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceUnpaywall 20191101
dc.subjectaluminum derivative
dc.subjectaluminum tetrafluoride
dc.subjectarginine
dc.subjectG protein coupled receptor
dc.subjectguanine nucleotide binding protein
dc.subjectguanosine triphosphatase
dc.subjectkb 1753
dc.subjectunclassified drug
dc.subjectguanine nucleotide binding protein alpha subunit
dc.subjectmutant protein
dc.subjectarticle
dc.subjectbinding affinity
dc.subjectbinding site
dc.subjectcontrolled study
dc.subjectcrystal structure
dc.subjectDNA binding motif
dc.subjectfungal strain
dc.subjectfungus
dc.subjectgene locus
dc.subjectgene mutation
dc.subjecthydrolysis
dc.subjectintracellular signaling
dc.subjectnonhuman
dc.subjectpathogenesis
dc.subjectprotein conformation
dc.subjectprotein protein interaction
dc.subjectsignal transduction
dc.subjectamino acid substitution
dc.subjectchemical structure
dc.subjectchemistry
dc.subjectenzyme active site
dc.subjectgenetics
dc.subjectHordeum
dc.subjectMagnaporthe
dc.subjectmetabolism
dc.subjectmicrobiology
dc.subjectmycosis
dc.subjectpathogenicity
dc.subjectphysiology
dc.subjectplant disease
dc.subjectplant leaf
dc.subjectpoint mutation
dc.subjectprotein folding
dc.subjectprotein tertiary structure
dc.subjectsignal transduction
dc.subjectX ray crystallography
dc.subjectFungi
dc.subjectMagnaporthe grisea
dc.subjectMagnaporthe oryzae
dc.subjectThespesia grandiflora
dc.subjectAmino Acid Substitution
dc.subjectCatalytic Domain
dc.subjectCrystallography, X-Ray
dc.subjectGTP-Binding Protein alpha Subunits
dc.subjectHordeum
dc.subjectMagnaporthe
dc.subjectModels, Molecular
dc.subjectMutant Proteins
dc.subjectMycoses
dc.subjectPlant Diseases
dc.subjectPlant Leaves
dc.subjectPoint Mutation
dc.subjectProtein Folding
dc.subjectProtein Structure, Tertiary
dc.subjectSignal Transduction
dc.typeArticle
dc.contributor.departmentDEPT OF BIOLOGICAL SCIENCES
dc.description.doi10.1371/journal.ppat.1002553
dc.description.sourcetitlePLoS Pathogens
dc.description.volume8
dc.description.issue2
dc.description.pagee1002553
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