6G2D

Citrate-induced acetyl-CoA carboxylase (ACC-Cit) filament at 5.4 A resolution


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 5.40 Å
  • Aggregation State: FILAMENT 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Structural basis for regulation of human acetyl-CoA carboxylase.

Hunkeler, M.Hagmann, A.Stuttfeld, E.Chami, M.Guri, Y.Stahlberg, H.Maier, T.

(2018) Nature 558: 470-474

  • DOI: https://doi.org/10.1038/s41586-018-0201-4
  • Primary Citation of Related Structures:  
    6G2D, 6G2H, 6G2I

  • PubMed Abstract: 

    Acetyl-CoA carboxylase catalyses the ATP-dependent carboxylation of acetyl-CoA, a rate-limiting step in fatty acid biosynthesis 1,2 . Eukaryotic acetyl-CoA carboxylases are large, homodimeric multienzymes. Human acetyl-CoA carboxylase occurs in two isoforms: the metabolic, cytosolic ACC1, and ACC2, which is anchored to the outer mitochondrial membrane and controls fatty acid β-oxidation 1,3 . ACC1 is regulated by a complex interplay of phosphorylation, binding of allosteric regulators and protein-protein interactions, which is further linked to filament formation 1,4-8 . These filaments were discovered in vitro and in vivo 50 years ago 7,9,10 , but the structural basis of ACC1 polymerization and regulation remains unknown. Here, we identify distinct activated and inhibited ACC1 filament forms. We obtained cryo-electron microscopy structures of an activated filament that is allosterically induced by citrate (ACC-citrate), and an inactivated filament form that results from binding of the BRCT domains of the breast cancer type 1 susceptibility protein (BRCA1). While non-polymeric ACC1 is highly dynamic, filament formation locks ACC1 into different catalytically competent or incompetent conformational states. This unique mechanism of enzyme regulation via large-scale conformational changes observed in ACC1 has potential uses in engineering of switchable biosynthetic systems. Dissecting the regulation of acetyl-CoA carboxylase opens new paths towards counteracting upregulation of fatty acid biosynthesis in disease.


  • Organizational Affiliation

    Biozentrum, University of Basel, Basel, Switzerland. moritz_hunkeler@dfci.harvard.edu.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Acetyl-CoA carboxylase 1A [auth B],
B [auth C],
C [auth D],
D [auth F]
2,407Homo sapiensMutation(s): 0 
Gene Names: ACACAACACACC1ACCA
EC: 6.4.1.2 (PDB Primary Data), 6.3.4.14 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for Q13085 (Homo sapiens)
Explore Q13085 
Go to UniProtKB:  Q13085
PHAROS:  Q13085
GTEx:  ENSG00000278540 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ13085
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 5.40 Å
  • Aggregation State: FILAMENT 
  • Reconstruction Method: SINGLE PARTICLE 
EM Software:
TaskSoftware PackageVersion
RECONSTRUCTIONRELION2.1b1

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Swiss National Science FoundationSwitzerland138262
Swiss National Science FoundationSwitzerland15696
Swiss National Science FoundationSwitzerland164074

Revision History  (Full details and data files)

  • Version 1.0: 2018-06-13
    Type: Initial release
  • Version 1.1: 2018-06-27
    Changes: Data collection, Database references
  • Version 1.2: 2019-11-06
    Changes: Data collection, Refinement description
  • Version 1.3: 2019-12-11
    Changes: Other