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- PDB-6g2i: Filament of acetyl-CoA carboxylase and BRCT domains of BRCA1 (ACC... -

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Basic information

Entry
Database: PDB / ID: 6g2i
TitleFilament of acetyl-CoA carboxylase and BRCT domains of BRCA1 (ACC-BRCT) at 5.9 A resolution
Components
  • Acetyl-CoA carboxylase 1
  • Breast cancer type 1 susceptibility protein
KeywordsLIGASE / Filament / Helical / Multienzyme / Biotin-dependent carboxylase
Function / homology
Function and homology information


fatty-acyl-CoA biosynthetic process / Defective HLCS causes multiple carboxylase deficiency / Biotin transport and metabolism / Defective DNA double strand break response due to BRCA1 loss of function / Defective DNA double strand break response due to BARD1 loss of function / : / BRCA1-BARD1 complex / acetyl-CoA carboxylase / BRCA1-C complex / BRCA1-B complex ...fatty-acyl-CoA biosynthetic process / Defective HLCS causes multiple carboxylase deficiency / Biotin transport and metabolism / Defective DNA double strand break response due to BRCA1 loss of function / Defective DNA double strand break response due to BARD1 loss of function / : / BRCA1-BARD1 complex / acetyl-CoA carboxylase / BRCA1-C complex / BRCA1-B complex / BRCA1-A complex / random inactivation of X chromosome / negative regulation of centriole replication / Fatty acyl-CoA biosynthesis / acetyl-CoA metabolic process / negative regulation of intracellular estrogen receptor signaling pathway / gamma-tubulin ring complex / malonyl-CoA biosynthetic process / nuclear ubiquitin ligase complex / acetyl-CoA carboxylase activity / ChREBP activates metabolic gene expression / DNA strand resection involved in replication fork processing / chordate embryonic development / negative regulation of fatty acid biosynthetic process / cellular response to indole-3-methanol / homologous recombination / lateral element / tissue homeostasis / XY body / protein K6-linked ubiquitination / regulation of DNA damage checkpoint / dosage compensation by inactivation of X chromosome / Carnitine metabolism / negative regulation of gene expression via chromosomal CpG island methylation / protein metabolic process / Impaired BRCA2 binding to PALB2 / : / mitotic G2/M transition checkpoint / postreplication repair / DNA repair complex / RNA polymerase binding / centrosome cycle / Defective homologous recombination repair (HRR) due to BRCA1 loss of function / Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function / Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function / Homologous DNA Pairing and Strand Exchange / Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) / Resolution of D-loop Structures through Holliday Junction Intermediates / HDR through Single Strand Annealing (SSA) / Impaired BRCA2 binding to RAD51 / intracellular non-membrane-bounded organelle / response to ionizing radiation / DNA-binding transcription activator activity / Transcriptional Regulation by E2F6 / lipid homeostasis / mitotic G2 DNA damage checkpoint signaling / Presynaptic phase of homologous DNA pairing and strand exchange / negative regulation of cell cycle / positive regulation of vascular endothelial growth factor production / negative regulation of reactive oxygen species metabolic process / localization / regulation of DNA repair / protein autoubiquitination / ubiquitin ligase complex / SUMOylation of DNA damage response and repair proteins / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / positive regulation of DNA repair / Meiotic synapsis / tubulin binding / Activation of gene expression by SREBF (SREBP) / male germ cell nucleus / chromosome segregation / cellular response to ionizing radiation / TP53 Regulates Transcription of DNA Repair Genes / Nonhomologous End-Joining (NHEJ) / double-strand break repair via homologous recombination / RING-type E3 ubiquitin transferase / HDR through Homologous Recombination (HRR) / G2/M DNA damage checkpoint / negative regulation of cell growth / Metalloprotease DUBs / fibrillar center / Meiotic recombination / cellular response to prostaglandin E stimulus / ubiquitin-protein transferase activity / fatty acid biosynthetic process / positive regulation of angiogenesis / intrinsic apoptotic signaling pathway in response to DNA damage / KEAP1-NFE2L2 pathway / double-strand break repair / actin cytoskeleton / p53 binding / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / chromosome / Neddylation / cellular response to tumor necrosis factor / Processing of DNA double-strand break ends / protein homotetramerization / Regulation of TP53 Activity through Phosphorylation / damaged DNA binding
Similarity search - Function
Breast cancer type 1 susceptibility protein (BRCA1) / BRCA1, serine-rich domain / BRCA1-associated / Serine-rich domain associated with BRCT / Acetyl-CoA carboxylase, central domain / : / : / Acetyl-CoA carboxylase, central region / Acetyl-CoA carboxylase, BT domain / Acetyl-coenzyme A carboxyltransferase, C-terminal ...Breast cancer type 1 susceptibility protein (BRCA1) / BRCA1, serine-rich domain / BRCA1-associated / Serine-rich domain associated with BRCT / Acetyl-CoA carboxylase, central domain / : / : / Acetyl-CoA carboxylase, central region / Acetyl-CoA carboxylase, BT domain / Acetyl-coenzyme A carboxyltransferase, C-terminal / Acetyl-coenzyme A (CoA) carboxyltransferase C-terminal domain profile. / Acetyl-coenzyme A carboxyltransferase, N-terminal / Acetyl-coenzyme A (CoA) carboxyltransferase N-terminal domain profile. / Acetyl-CoA carboxylase / Carboxyl transferase domain / Biotin-binding site / Biotin-requiring enzymes attachment site. / Biotin carboxylase-like, N-terminal domain / Biotin carboxylase, C-terminal / Biotin carboxylation domain / Biotin carboxylase, N-terminal domain / Biotin carboxylase C-terminal domain / Biotin carboxylation domain profile. / Biotin carboxylase C-terminal domain / Carbamoyl-phosphate synthase subdomain signature 1. / Carbamoyl-phosphate synthetase large subunit-like, ATP-binding domain / Carbamoyl-phosphate synthase L chain, ATP binding domain / Biotin-requiring enzyme / Biotinyl/lipoyl domain profile. / Biotin/lipoyl attachment / Rudiment single hybrid motif / Single hybrid motif / Zinc finger, C3HC4 RING-type / Zinc finger, C3HC4 type (RING finger) / ATP-grasp fold, subdomain 1 / BRCA1 C Terminus (BRCT) domain / Pre-ATP-grasp domain superfamily / ATP-grasp fold / ATP-grasp fold profile. / breast cancer carboxy-terminal domain / ClpP/crotonase-like domain superfamily / Zinc finger, RING-type, conserved site / Zinc finger RING-type signature. / BRCT domain profile. / BRCT domain / BRCT domain superfamily / Ring finger / Zinc finger RING-type profile. / Zinc finger, RING-type / Carbamoyl-phosphate synthase subdomain signature 2. / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
Breast cancer type 1 susceptibility protein / Acetyl-CoA carboxylase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 5.9 Å
AuthorsHunkeler, M. / Hagmann, A. / Stuttfeld, E. / Chami, M. / Stahlberg, H. / Maier, T.
Funding support Switzerland, 3items
OrganizationGrant numberCountry
Swiss National Science Foundation138262 Switzerland
Swiss National Science Foundation15696 Switzerland
Swiss National Science Foundation164074 Switzerland
CitationJournal: Nature / Year: 2018
Title: Structural basis for regulation of human acetyl-CoA carboxylase.
Authors: Moritz Hunkeler / Anna Hagmann / Edward Stuttfeld / Mohamed Chami / Yakir Guri / Henning Stahlberg / Timm Maier /
Abstract: Acetyl-CoA carboxylase catalyses the ATP-dependent carboxylation of acetyl-CoA, a rate-limiting step in fatty acid biosynthesis. Eukaryotic acetyl-CoA carboxylases are large, homodimeric multienzymes. ...Acetyl-CoA carboxylase catalyses the ATP-dependent carboxylation of acetyl-CoA, a rate-limiting step in fatty acid biosynthesis. 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. ACC1 is regulated by a complex interplay of phosphorylation, binding of allosteric regulators and protein-protein interactions, which is further linked to filament formation. These filaments were discovered in vitro and in vivo 50 years ago, 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.
History
DepositionMar 23, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 13, 2018Provider: repository / Type: Initial release
Revision 1.1Jun 27, 2018Group: Data collection / Database references / Category: citation / em_software
Item: _citation.journal_id_ISSN / _citation.journal_volume ..._citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _em_software.name
Revision 1.2Nov 6, 2019Group: Data collection / Refinement description / Category: software / Item: _software.name
Revision 1.3Dec 11, 2019Group: Other / Category: atom_sites
Item: _atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] / _atom_sites.fract_transf_matrix[3][3]

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Structure visualization

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Assembly

Deposited unit
D: Acetyl-CoA carboxylase 1
E: Acetyl-CoA carboxylase 1
C: Acetyl-CoA carboxylase 1
F: Acetyl-CoA carboxylase 1
B: Acetyl-CoA carboxylase 1
A: Acetyl-CoA carboxylase 1
G: Acetyl-CoA carboxylase 1
Q: Acetyl-CoA carboxylase 1
J: Acetyl-CoA carboxylase 1
R: Acetyl-CoA carboxylase 1
H: Breast cancer type 1 susceptibility protein
K: Breast cancer type 1 susceptibility protein
M: Breast cancer type 1 susceptibility protein
O: Breast cancer type 1 susceptibility protein
S: Breast cancer type 1 susceptibility protein
U: Breast cancer type 1 susceptibility protein
Y: Breast cancer type 1 susceptibility protein
W: Breast cancer type 1 susceptibility protein


Theoretical massNumber of molelcules
Total (without water)2,880,81218
Polymers2,880,81218
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area100260 Å2
ΔGint-582 kcal/mol
Surface area808040 Å2
MethodPISA

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Components

#1: Protein
Acetyl-CoA carboxylase 1 / / ACC1 / ACC-alpha


Mass: 265949.344 Da / Num. of mol.: 10
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACACA, ACAC, ACC1, ACCA / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q13085, acetyl-CoA carboxylase, biotin carboxylase
#2: Protein
Breast cancer type 1 susceptibility protein / RING finger protein 53 / RING-type E3 ubiquitin transferase BRCA1


Mass: 27664.869 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRCA1, RNF53 / Production host: Escherichia coli (E. coli)
References: UniProt: P38398, RING-type E3 ubiquitin transferase

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1acetyl-CoA carboxylase and BRCTCOMPLEXall0MULTIPLE SOURCES
2Acetyl-CoA carboxylase 1COMPLEX#11RECOMBINANT
3Breast cancer type 1 susceptibility proteinCOMPLEX#21RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Spodoptera frugiperda (fall armyworm)7108
23Escherichia coli (E. coli)562
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 1 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)
Details: Collected in movie-mode with total dose of 80 e-/A2 for a total of 80 frames. Frames 3-22 were used for final reconstruction

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
PHENIX1.11.1_2575refinement
EM software
IDNameVersionCategoryDetails
8PHENIXmodel refinementThe clash score value (5.6) reported in the publication associated with this model was obtained directly from phenix.real_space_refine version 1.11.1-2575. We acknowledge that the current validation toolchain of wwwPDB produces slightly higher values, possibly linked to the handling of cif files (required as this submission contains more than 100.000 atoms) and protons and have locally reproduced this difference by using earlier software versions.
13RELION2.013D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 5.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 48483 / Symmetry type: POINT
RefinementStereochemistry target values: GeoStd + Monomer Library
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00959351679389291928
ELECTRON MICROSCOPYf_angle_d2.22227057957527316
ELECTRON MICROSCOPYf_chiral_restr0.12556837013722524
ELECTRON MICROSCOPYf_plane_restr0.0081374560217544930
ELECTRON MICROSCOPYf_dihedral_angle_d10.5746762601117074

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