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Title: Crystal structure of the 500-kDa yeast acetyl-CoA carboxylase holoenzyme dimer

Abstract

Acetyl-CoA carboxylase (ACC) has crucial roles in fatty acid metabolism and is an attractive target for drug discovery against diabetes, cancer and other diseases1, 2, 3, 4, 5, 6. Saccharomyces cerevisiae ACC (ScACC) is crucial for the production of very-long-chain fatty acids and the maintenance of the nuclear envelope7, 8. ACC contains biotin carboxylase (BC) and carboxyltransferase (CT) activities, and its biotin is linked covalently to the biotin carboxyl carrier protein (BCCP). Most eukaryotic ACCs are 250-kilodalton (kDa), multi-domain enzymes and function as homodimers and higher oligomers. They contain a unique, 80-kDa central region that shares no homology with other proteins. Although the structures of the BC, CT and BCCP domains and other biotin-dependent carboxylase holoenzymes are known1, 9, 10, 11, 12, 13, 14, there is currently no structural information on the ACC holoenzyme. Here we report the crystal structure of the full-length, 500-kDa holoenzyme dimer of ScACC. The structure is remarkably different from that of the other biotin-dependent carboxylases. The central region contains five domains and is important for positioning the BC and CT domains for catalysis. The structure unexpectedly reveals a dimer of the BC domain and extensive conformational differences compared to the structure of the BC domainmore » alone, which is a monomer. These structural changes reveal why the BC domain alone is catalytically inactive and define the molecular mechanism for the inhibition of eukaryotic ACC by the natural product soraphen A15, 16 and by phosphorylation of a Ser residue just before the BC domain core in mammalian ACC. The BC and CT active sites are separated by 80 Å, and the entire BCCP domain must translocate during catalysis.« less

Authors:
;
Publication Date:
Research Org.:
Brookhaven National Lab. (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1354314
Report Number(s):
BNL-112830-2016-JA
Journal ID: ISSN 0028-0836
DOE Contract Number:  
SC00112704
Resource Type:
Journal Article
Journal Name:
Nature (London)
Additional Journal Information:
Journal Volume: 526; Journal Issue: 7575; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; x-ray crystallography; fatty acids

Citation Formats

Wei, Jia, and Tong, Liang. Crystal structure of the 500-kDa yeast acetyl-CoA carboxylase holoenzyme dimer. United States: N. p., 2015. Web. doi:10.1038/nature15375.
Wei, Jia, & Tong, Liang. Crystal structure of the 500-kDa yeast acetyl-CoA carboxylase holoenzyme dimer. United States. https://doi.org/10.1038/nature15375
Wei, Jia, and Tong, Liang. Mon . "Crystal structure of the 500-kDa yeast acetyl-CoA carboxylase holoenzyme dimer". United States. https://doi.org/10.1038/nature15375.
@article{osti_1354314,
title = {Crystal structure of the 500-kDa yeast acetyl-CoA carboxylase holoenzyme dimer},
author = {Wei, Jia and Tong, Liang},
abstractNote = {Acetyl-CoA carboxylase (ACC) has crucial roles in fatty acid metabolism and is an attractive target for drug discovery against diabetes, cancer and other diseases1, 2, 3, 4, 5, 6. Saccharomyces cerevisiae ACC (ScACC) is crucial for the production of very-long-chain fatty acids and the maintenance of the nuclear envelope7, 8. ACC contains biotin carboxylase (BC) and carboxyltransferase (CT) activities, and its biotin is linked covalently to the biotin carboxyl carrier protein (BCCP). Most eukaryotic ACCs are 250-kilodalton (kDa), multi-domain enzymes and function as homodimers and higher oligomers. They contain a unique, 80-kDa central region that shares no homology with other proteins. Although the structures of the BC, CT and BCCP domains and other biotin-dependent carboxylase holoenzymes are known1, 9, 10, 11, 12, 13, 14, there is currently no structural information on the ACC holoenzyme. Here we report the crystal structure of the full-length, 500-kDa holoenzyme dimer of ScACC. The structure is remarkably different from that of the other biotin-dependent carboxylases. The central region contains five domains and is important for positioning the BC and CT domains for catalysis. The structure unexpectedly reveals a dimer of the BC domain and extensive conformational differences compared to the structure of the BC domain alone, which is a monomer. These structural changes reveal why the BC domain alone is catalytically inactive and define the molecular mechanism for the inhibition of eukaryotic ACC by the natural product soraphen A15, 16 and by phosphorylation of a Ser residue just before the BC domain core in mammalian ACC. The BC and CT active sites are separated by 80 Å, and the entire BCCP domain must translocate during catalysis.},
doi = {10.1038/nature15375},
url = {https://www.osti.gov/biblio/1354314}, journal = {Nature (London)},
issn = {0028-0836},
number = 7575,
volume = 526,
place = {United States},
year = {2015},
month = {10}
}