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- PDB-9c3c: Cryo-EM structure of native dystrophin-glycoprotein complex (DGC) -

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Basic information

Entry
Database: PDB / ID: 9c3c
TitleCryo-EM structure of native dystrophin-glycoprotein complex (DGC)
Components
  • Alpha-dystroglycan
  • Alpha-sarcoglycan
  • Beta-dystroglycan
  • Beta-sarcoglycan
  • Dystrobrevin
  • Dystrophin
  • Gamma-sarcoglycan
  • Sarcoglycan delta
  • Sarcospan
KeywordsMEMBRANE PROTEIN / beta-helix / sarcolemma / glycosylation / muscular dystrophy
Function / homology
Function and homology information


sarcoglycan complex / muscle attachment / dystroglycan complex / nerve maturation / retrograde trans-synaptic signaling by trans-synaptic protein complex / positive regulation of basement membrane assembly involved in embryonic body morphogenesis / contractile ring / regulation of gastrulation / morphogenesis of an epithelial sheet / coronary vasculature morphogenesis ...sarcoglycan complex / muscle attachment / dystroglycan complex / nerve maturation / retrograde trans-synaptic signaling by trans-synaptic protein complex / positive regulation of basement membrane assembly involved in embryonic body morphogenesis / contractile ring / regulation of gastrulation / morphogenesis of an epithelial sheet / coronary vasculature morphogenesis / dystrophin-associated glycoprotein complex / microtubule anchoring / laminin-1 binding / basement membrane organization / regulation of epithelial to mesenchymal transition / photoreceptor ribbon synapse / dystroglycan binding / vinculin binding / myelination in peripheral nervous system / branching involved in salivary gland morphogenesis / commissural neuron axon guidance / protein-containing complex localization / node of Ranvier / cardiac muscle cell contraction / cardiac muscle tissue development / cardiac muscle cell development / structural constituent of muscle / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / muscle organ development / regulation of synapse organization / response to muscle activity / heart contraction / epithelial tube branching involved in lung morphogenesis / alpha-actinin binding / membrane protein ectodomain proteolysis / basement membrane / : / negative regulation of MAPK cascade / heart morphogenesis / calcium ion homeostasis / tubulin binding / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / SH2 domain binding / negative regulation of cell migration / sarcoplasmic reticulum / GABA-ergic synapse / filopodium / calcium-mediated signaling / sarcolemma / regulation of synaptic plasticity / protein transport / cell-cell junction / lamellipodium / actin binding / virus receptor activity / postsynaptic membrane / cytoskeleton / intracellular signal transduction / membrane raft / external side of plasma membrane / focal adhesion / calcium ion binding / protein-containing complex binding / extracellular space / extracellular region / nucleoplasm / plasma membrane / cytoplasm
Similarity search - Function
Sarcoglycan complex subunit protein / Sarcoglycan alpha/epsilon / Beta-sarcoglycan / Sarcospan / Sarcoglycan gamma/delta/zeta / : / : / Sarcoglycan complex subunit protein / Sarcoglycan alpha/epsilon N-terminal domain / Sarcoglycan alpha/epsilon second domain ...Sarcoglycan complex subunit protein / Sarcoglycan alpha/epsilon / Beta-sarcoglycan / Sarcospan / Sarcoglycan gamma/delta/zeta / : / : / Sarcoglycan complex subunit protein / Sarcoglycan alpha/epsilon N-terminal domain / Sarcoglycan alpha/epsilon second domain / Dystroglycan-type cadherin-like / Dystroglycan, C-terminal / Alpha-dystroglycan domain 2 / DG-type SEA domain / Alpha-dystroglycan N-terminal domain 2 / Dystroglycan (Dystrophin-associated glycoprotein 1) / Alpha-Dystroglycan N-terminal domain 2 / DG-type SEA domain profile. / Dystroglycan-type cadherin-like domains. / Putative Ig domain / CD20-like family / CD20-like family / Cadherin-like superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Sarcoglycan delta / Sarcospan / Beta-sarcoglycan / Gamma-sarcoglycan / Dystroglycan 1 / Alpha-sarcoglycan
Similarity search - Component
Biological speciesOryctolagus cuniculus (rabbit)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.3 Å
AuthorsLiu, S. / Su, T. / Xia, X. / Zhou, Z.H.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM071940 United States
CitationJournal: Nature / Year: 2025
Title: Native DGC structure rationalizes muscular dystrophy-causing mutations.
Authors: Shiheng Liu / Tiantian Su / Xian Xia / Z Hong Zhou /
Abstract: Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder marked by progressive muscle wasting leading to premature mortality. Discovery of the DMD gene encoding dystrophin both ...Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder marked by progressive muscle wasting leading to premature mortality. Discovery of the DMD gene encoding dystrophin both revealed the cause of DMD and helped identify a family of at least ten dystrophin-associated proteins at the muscle cell membrane, collectively forming the dystrophin-glycoprotein complex (DGC). The DGC links the extracellular matrix to the cytoskeleton, but, despite its importance, its molecular architecture has remained elusive. Here we determined the native cryo-electron microscopy structure of rabbit DGC and conducted biochemical analyses to reveal its intricate molecular configuration. An unexpected β-helix comprising β-, γ- and δ-sarcoglycan forms an extracellular platform that interacts with α-dystroglycan, β-dystroglycan and α-sarcoglycan, allowing α-dystroglycan to contact the extracellular matrix. In the membrane, sarcospan anchors β-dystroglycan to the β-, γ- and δ-sarcoglycan trimer, while in the cytoplasm, β-dystroglycan's juxtamembrane fragment binds dystrophin's ZZ domain. Through these interactions, the DGC links laminin 2 to intracellular actin. Additionally, dystrophin's WW domain, along with its EF-hand 1 domain, interacts with α-dystrobrevin. A disease-causing mutation mapping to the WW domain weakens this interaction, as confirmed by deletion of the WW domain in biochemical assays. Our findings rationalize more than 110 mutations affecting single residues associated with various muscular dystrophy subtypes and contribute to ongoing therapeutic developments, including protein restoration, upregulation of compensatory genes and gene replacement.
History
DepositionMay 31, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 23, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update
Revision 1.2Dec 25, 2024Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update
Revision 1.3Feb 12, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Alpha-dystroglycan
B: Beta-dystroglycan
D: Dystrophin
a: Alpha-sarcoglycan
b: Beta-sarcoglycan
d: Sarcoglycan delta
g: Gamma-sarcoglycan
n: Sarcospan
V: Dystrobrevin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)769,84519
Polymers764,8729
Non-polymers4,97310
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 9 types, 9 molecules ABDabdgnV

#1: Protein Alpha-dystroglycan / Beta-DG


Mass: 67623.688 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit) / References: UniProt: Q28685
#2: Protein Beta-dystroglycan / Beta-DG


Mass: 15714.142 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit) / References: UniProt: Q28685
#3: Protein Dystrophin


Mass: 427942.781 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit)
#4: Protein Alpha-sarcoglycan / Alpha-SG / 50 kDa dystrophin-associated glycoprotein / 50DAG / Adhalin / Dystroglycan-2


Mass: 35969.039 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit) / References: UniProt: Q28686
#5: Protein Beta-sarcoglycan / Beta-SG


Mass: 34768.695 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit) / References: UniProt: Q28635
#6: Protein Sarcoglycan delta


Mass: 32142.350 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit) / References: UniProt: G1SGL0
#7: Protein Gamma-sarcoglycan


Mass: 32005.486 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit) / References: UniProt: Q28646
#8: Protein Sarcospan


Mass: 26058.631 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit) / References: UniProt: P82352
#9: Protein Dystrobrevin


Mass: 92647.117 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit)

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Sugars , 3 types, 10 molecules

#10: Polysaccharide
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 7 / Source method: obtained synthetically
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#11: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#12: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: dystrophin-glycoprotein complex (DGC) / Type: COMPLEX / Entity ID: #1, #3, #5, #8-#9 / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Oryctolagus cuniculus (rabbit)
Buffer solutionpH: 7.4
Details: 150 mM NaCl, 0.1% digitonin, 50 mM Tris-HCl, pH 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: PELCO Ultrathin Carbon with Lacey Carbon
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 281.15 K

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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 FIELD / Nominal defocus max: 3000 nm / Nominal defocus min: 1500 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recording
IDImaging-IDElectron dose (e/Å2)Detector modeFilm or detector model
1150SUPER-RESOLUTIONGATAN K2 SUMMIT (4k x 4k)
2150GATAN K3 BIOQUANTUM (6k x 4k)
EM imaging opticsEnergyfilter name: GIF Quantum LS / Energyfilter slit width: 20 eV

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Processing

EM software
IDNameCategory
2SerialEMimage acquisition
4CTFFINDCTF correction
7UCSF Chimeramodel fitting
8UCSF ChimeraXmodel fitting
9Cootmodel fitting
11cryoSPARCinitial Euler assignment
12cryoSPARCfinal Euler assignment
13cryoSPARCclassification
14cryoSPARC3D reconstruction
15PHENIXmodel refinement
Image processingDetails: both K2 and K3 detector were used for this reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 134481 / Symmetry type: POINT
Atomic model buildingSpace: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00319856
ELECTRON MICROSCOPYf_angle_d0.64626949
ELECTRON MICROSCOPYf_dihedral_angle_d5.0392811
ELECTRON MICROSCOPYf_chiral_restr0.053180
ELECTRON MICROSCOPYf_plane_restr0.0053418

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