NDLI: Crystal structure of the 500 kD yeast acetyl-CoA carboxylase holoenzyme dimer

Content Provider	PubMed Central
Author	Wei, Jia Tong, Liang
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 diseases 1–6 . Saccharomyces cerevisiae ACC (ScACC) is crucial for the production of very-long-chain fatty acids and the maintenance of the nuclear envelope 7,8 . 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 kD, multi-domain enzymes and function as homo-dimers and higher oligomers. They contain a unique, 80 kD central region that shares no homology with other proteins. While the structures of the BC, CT and BCCP domains and other biotin-dependent carboxylase holoenzymes are known 1,9–14 , currently there is no structural information on the ACC holoenzyme. Here we report the crystal structure of the full-length, 500 kD holoenzyme dimer of ScACC. The structure is strikingly different from those 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 BC domain alone, which is a monomer. These structural changes explain why the BC domain alone is catalytically inactive and define the molecular mechanism for the inhibition of eukaryotic ACC by the natural product soraphen A 15,16 and by phosphorylation of a Ser residue just prior to 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.
Related Links	http://dx.doi.org/10.1038/nature15375
Ending Page	727
Page Count	5
Starting Page	723
File Format	PDF
ISSN	00280836
e-ISSN	14764687
Journal	Nature
Issue Number	7575
Volume Number	526
Language	English
Publisher Date	2015-10-01
Access Restriction	Open
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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