Plant Molecular Biology

, Volume 81, Issue 4–5, pp 431–446 | Cite as

Structural, kinetic and computational investigation of Vitis vinifera DHDPS reveals new insight into the mechanism of lysine-mediated allosteric inhibition

  • Sarah C. Atkinson
  • Con Dogovski
  • Matthew T. Downton
  • Peter E. Czabotar
  • Renwick C. J. Dobson
  • Juliet A. Gerrard
  • John Wagner
  • Matthew A. Perugini
Article

Abstract

Lysine is one of the most limiting amino acids in plants and its biosynthesis is carefully regulated through inhibition of the first committed step in the pathway catalyzed by dihydrodipicolinate synthase (DHDPS). This is mediated via a feedback mechanism involving the binding of lysine to the allosteric cleft of DHDPS. However, the precise allosteric mechanism is yet to be defined. We present a thorough enzyme kinetic and thermodynamic analysis of lysine inhibition of DHDPS from the common grapevine, Vitis vinifera (Vv). Our studies demonstrate that lysine binding is both tight (relative to bacterial DHDPS orthologs) and cooperative. The crystal structure of the enzyme bound to lysine (2.4 Å) identifies the allosteric binding site and clearly shows a conformational change of several residues within the allosteric and active sites. Molecular dynamics simulations comparing the lysine-bound (PDB ID 4HNN) and lysine free (PDB ID 3TUU) structures show that Tyr132, a key catalytic site residue, undergoes significant rotational motion upon lysine binding. This suggests proton relay through the catalytic triad is attenuated in the presence of lysine. Our study reveals for the first time the structural mechanism for allosteric inhibition of DHDPS from the common grapevine.

Keywords

Allostery Analytical ultracentrifugation Circular dichroism spectroscopy Dihydrodipicolinate synthase Enzyme Grapevine Lysine biosynthesis Molecular dynamics simulations X-ray crystallography 
ASA

(S)-Aspartate semialdehyde

DHDPR

Dihydrodipicolinate reductase

DHDPS

Dihydrodipicolinate synthase

Pyr

Pyruvate

Lysine

(S)-Lysine

Threonine

(S)-Threonine

Vv

Vitis vinifera

Notes

Acknowledgments

We would firstly like to acknowledge the support and assistance of the friendly staff at the Bio21 Collaborative Crystallographic Centre at CSIRO Molecular and Health Technologies, Parkville, Melbourne and the beamline scientists at the Australian Synchrotron, Victoria, Australia. We would also like to thank all members of the Perugini laboratory for helpful discussions during the preparation of this manuscript. Finally, we acknowledge the Australian Research Council for providing a Future Fellowship for M.A.P. and P.C and the University of Melbourne (FRGSS 2011 Project grant) for project funding. R.C.J.D. acknowledges the CR Roper Bequest for Fellowship support. This research was supported by a Victorian Life Sciences Computation Initiative (VLSCI) grant number VR0089 on its Peak Computing Facility at the University of Melbourne, an initiative of the Victorian Government, Australia.

Supplementary material

11103_2013_14_MOESM1_ESM.docx (10 mb)
Supplementary material 1 (DOCX 10199 kb)

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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Sarah C. Atkinson
    • 1
    • 2
  • Con Dogovski
    • 1
  • Matthew T. Downton
    • 3
  • Peter E. Czabotar
    • 4
  • Renwick C. J. Dobson
    • 2
    • 5
  • Juliet A. Gerrard
    • 5
    • 6
  • John Wagner
    • 3
  • Matthew A. Perugini
    • 1
    • 2
  1. 1.Department of Biochemistry, La Trobe Institute for Molecular ScienceLa Trobe UniversityMelbourneAustralia
  2. 2.Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology InstituteThe University of MelbourneMelbourneAustralia
  3. 3.IBM Research Collaboratory for Life Sciences-MelbourneVictorian Life Sciences Computation InitiativeCarltonAustralia
  4. 4.The Walter and Eliza Hall Institute of Medical ResearchParkvilleAustralia
  5. 5.Biomolecular Interaction Centre and School of Biological SciencesUniversity of CanterburyChristchurchNew Zealand
  6. 6.Industrial Research LimitedLower HuttNew Zealand

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