Evolution of quaternary structure in a homotetrameric enzyme

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dc.contributor.authorGriffin, MDWen_AU
dc.contributor.authorDobson, RCJen_AU
dc.contributor.authorPearce, FGen_AU
dc.contributor.authorAntonio, Len_AU
dc.contributor.authorWhitten, AEen_AU
dc.contributor.authorLiew, Ken_AU
dc.contributor.authorMackay, JPen_AU
dc.contributor.authorTrewhella, Jen_AU
dc.contributor.authorJameson, GBen_AU
dc.contributor.authorPerugini, MAen_AU
dc.contributor.authorGerrard, JAen_AU
dc.date.accessioned2009-10-08T01:05:51Zen_AU
dc.date.accessioned2010-04-30T05:06:04Zen_AU
dc.date.available2009-10-08T01:05:51Zen_AU
dc.date.available2010-04-30T05:06:04Zen_AU
dc.date.issued2008-07-18en_AU
dc.date.statistics2008-07-18en_AU
dc.description.abstractDihydrodipicolinate synthase (DHDPS) is an essential enzyme in (S)-lysine biosynthesis and an important antibiotic target. All X-ray crystal structures solved to date reveal a homotetrameric enzyme. In order to explore the role of this quaternary structure, dimeric variants of Escherichia coli DHDPS were engineered and their properties were compared to those of the wild-type tetrameric form. X-ray crystallography reveals that the active site is not disturbed when the quaternary structure is disrupted. However, the activity of the dimeric enzymes in solution is substantially reduced, and a tetrahedral adduct of a substrate analogue is observed to be trapped at the active site in the crystal form. Remarkably, heating the dimeric enzymes increases activity. We propose that the homotetrameric structure of DHDPS reduces dynamic fluctuations present in the dimeric forms and increases specificity for the first substrate, pyruvate. By restricting motion in a key catalytic motif, a competing, non-productive reaction with a substrate analogue is avoided. Small-angle X-ray scattering and mutagenesis data, together with a B-factor analysis of the crystal structures, support this hypothesis and lead to the suggestion that in at least some cases, the evolution of quaternary enzyme structures might serve to optimise the dynamic properties of the protein subunits. © 2008, Elsevier Ltd.en_AU
dc.identifier.citationGriffin, M. D. W., Dobson, R. C. J., Pearce, F. G., Antonio, L., Whitten, A. E., Liew, K., Mackay, J. P. Trewhella, J., Jameson, G. B., Perugini, M. A., & Gerrard, J. A. (2008). Evolution of quaternary structure in a homotetrameric enzyme. Journal of Molecular Biology, 380(4), 691-703. doi:10.1016/j.jmb.2008.05.038en_AU
dc.identifier.govdoc1389en_AU
dc.identifier.issn0022-2836en_AU
dc.identifier.issue4en_AU
dc.identifier.journaltitleJournal of Molecular Biologyen_AU
dc.identifier.pagination691-703en_AU
dc.identifier.urihttp://dx.doi.org/10.1016/j.jmb.2008.05.038en_AU
dc.identifier.urihttp://apo.ansto.gov.au/dspace/handle/10238/1973en_AU
dc.identifier.volume380en_AU
dc.language.isoenen_AU
dc.publisherElsevieren_AU
dc.subjectEnzymesen_AU
dc.subjectCrystal structureen_AU
dc.subjectSmall angle scatteringen_AU
dc.subjectQuaternary compoundsen_AU
dc.subjectCrystallographyen_AU
dc.subjectEscherichia colien_AU
dc.titleEvolution of quaternary structure in a homotetrameric enzymeen_AU
dc.typeJournal Articleen_AU
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