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Title: Allosteric Motions in Structures of Yeast NAD+-Specific Isocitrate Dehydrogenase

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.

Authors:
; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
959571
Report Number(s):
BNL-82557-2009-JA
Journal ID: ISSN 0021-9258; JBCHA3; TRN: US201016%%715
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
Journal Volume: 283; Journal Issue: 16; Journal ID: ISSN 0021-9258
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; CITRATES; COMMUNICATIONS; DISULFIDES; ENERGY LEVELS; ENZYMES; OXIDOREDUCTASES; PHOSPHORYLATION; REGULATIONS; YEASTS; LIGANDS; national synchrotron light source

Citation Formats

Taylor,A., Hu, G., Hart, P., and McAlister-Henn, L. Allosteric Motions in Structures of Yeast NAD+-Specific Isocitrate Dehydrogenase. United States: N. p., 2008. Web. doi:10.1074/jbc.M708719200.
Taylor,A., Hu, G., Hart, P., & McAlister-Henn, L. Allosteric Motions in Structures of Yeast NAD+-Specific Isocitrate Dehydrogenase. United States. doi:10.1074/jbc.M708719200.
Taylor,A., Hu, G., Hart, P., and McAlister-Henn, L. Tue . "Allosteric Motions in Structures of Yeast NAD+-Specific Isocitrate Dehydrogenase". United States. doi:10.1074/jbc.M708719200.
@article{osti_959571,
title = {Allosteric Motions in Structures of Yeast NAD+-Specific Isocitrate Dehydrogenase},
author = {Taylor,A. and Hu, G. and Hart, P. and McAlister-Henn, L.},
abstractNote = {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.},
doi = {10.1074/jbc.M708719200},
journal = {Journal of Biological Chemistry},
issn = {0021-9258},
number = 16,
volume = 283,
place = {United States},
year = {2008},
month = {1}
}