Exploring the dihydrodipicolinate synthase tetramer: How resilient is the dimer–dimer interface?

Exploring the dihydrodipicolinate synthase tetramer: How resilient is the dimer–dimer interface? Dihydrodipicolinate synthase (DHDPS, E.C. 4.2.1.52) is a tetrameric enzyme that catalyses the first committed step of the lysine biosynthetic pathway. Dimeric variants of DHDPS have impaired catalytic activity due to aberrant protein motions within the dimer unit. Thus, it is thought that the tetrameric structure functions to restrict these motions and optimise enzyme dynamics for catalysis. Despite the importance of dimer–dimer association, the interface between subunits of each dimer is small, accounting for only 4.3% of the total monomer surface area, and the structure of the interface is not conserved across species. We have probed the tolerance of dimer–dimer association to mutation by introducing amino acid substitutions within the interface. All point mutations resulted in destabilisation of the ‘dimer of dimers’ tetrameric structure. Both the position of the mutation in the interface and the physico-chemical nature of the substitution appeared to effect tetramerisation. Despite only weak destabilisation of the tetramer by some mutations, catalytic activity was reduced to ∼10–15% of the wild-type in all cases, suggesting that the dimer–dimer interface is finely tuned to optimise function. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Biochemistry and Biophysics Elsevier

Exploring the dihydrodipicolinate synthase tetramer: How resilient is the dimer–dimer interface?

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Publisher
Elsevier
Copyright
Copyright © 2009 Elsevier Inc.
ISSN
0003-9861
eISSN
1096-0384
D.O.I.
10.1016/j.abb.2009.11.014
Publisher site
See Article on Publisher Site

Abstract

Dihydrodipicolinate synthase (DHDPS, E.C. 4.2.1.52) is a tetrameric enzyme that catalyses the first committed step of the lysine biosynthetic pathway. Dimeric variants of DHDPS have impaired catalytic activity due to aberrant protein motions within the dimer unit. Thus, it is thought that the tetrameric structure functions to restrict these motions and optimise enzyme dynamics for catalysis. Despite the importance of dimer–dimer association, the interface between subunits of each dimer is small, accounting for only 4.3% of the total monomer surface area, and the structure of the interface is not conserved across species. We have probed the tolerance of dimer–dimer association to mutation by introducing amino acid substitutions within the interface. All point mutations resulted in destabilisation of the ‘dimer of dimers’ tetrameric structure. Both the position of the mutation in the interface and the physico-chemical nature of the substitution appeared to effect tetramerisation. Despite only weak destabilisation of the tetramer by some mutations, catalytic activity was reduced to ∼10–15% of the wild-type in all cases, suggesting that the dimer–dimer interface is finely tuned to optimise function.

Journal

Archives of Biochemistry and BiophysicsElsevier

Published: Feb 1, 2010

References

  • J. Mol. Biol.
    Mirwaldt, C.; Korndorfer, I.; Huber, R.
  • Chembiochem
    Phenix, C.P.; Nienaber, K.; Tam, P.H.; Delbaere, L.T.; Palmer, D.R.
  • J. Mol. Biol.
    Blickling, S.; Beisel, H.; Bozic, D.; Knablein, J.; Laber, B.; Huber, R.

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