Allosteric motions in structures of yeast NAD+-specific isocitrate dehydrogenase

Alexander B. Taylor, Gang Hu, P. John Hart, Lee McAlister-Henn

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Mitochondrial NAD+-specific isocitrate dehydrogenases (IDHs) are key regulators of flux through biosynthetic and oxidative pathways in response to cellular energy levels. Here we present the first structures of a eukaryotic member of this enzyme family, the allosteric, hetero-octameric, NAD +-specific IDH from yeast in three forms: 1) without ligands, 2) with bound analog citrate, and 3) with bound citrate + AMP. The structures reveal the molecular basis for ligand binding to homologous but distinct regulatory and catalytic sites positioned at the interfaces between IDH1 and IDH2 subunits and define pathways of communication between heterodimers and heterotetramers in the hetero-octamer. Disulfide bonds observed at the heterotetrameric interfaces in the unliganded IDH hetero-octamer are reduced in the ligand-bound forms, suggesting a redox regulatory mechanism that may be analogous to the "on-off" regulation of non-allosteric bacterial IDHs via phosphorylation. The results strongly suggest that eukaryotic IDH enzymes are exquisitely tuned to ensure that allosteric activation occurs only when concentrations of isocitrate are elevated.

Original languageEnglish (US)
Pages (from-to)10872-10880
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number16
DOIs
StatePublished - Apr 18 2008

Fingerprint

Isocitrate Dehydrogenase
NAD
Yeast
Yeasts
Ligands
Citric Acid
Allosteric Regulation
Phosphorylation
Biosynthetic Pathways
Enzymes
Adenosine Monophosphate
Molecular Structure
Disulfides
Electron energy levels
Oxidation-Reduction
Catalytic Domain
Chemical activation
Communication
Fluxes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Allosteric motions in structures of yeast NAD+-specific isocitrate dehydrogenase. / Taylor, Alexander B.; Hu, Gang; Hart, P. John; McAlister-Henn, Lee.

In: Journal of Biological Chemistry, Vol. 283, No. 16, 18.04.2008, p. 10872-10880.

Research output: Contribution to journalArticle

Taylor, Alexander B. ; Hu, Gang ; Hart, P. John ; McAlister-Henn, Lee. / Allosteric motions in structures of yeast NAD+-specific isocitrate dehydrogenase. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 16. pp. 10872-10880.
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