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- PDB-8yt8: Cryo-EM structure of the dystrophin glycoprotein complex -

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Basic information

Entry
Database: PDB / ID: 8yt8
TitleCryo-EM structure of the dystrophin glycoprotein complex
Components
  • Alpha-sarcoglycan
  • Beta-dystroglycan
  • Beta-sarcoglycan
  • Delta-sarcoglycan
  • Dystrobrevin alpha
  • Dystrophin
  • Gamma-sarcoglycan
  • Sarcospan
  • unknown segment
KeywordsSTRUCTURAL PROTEIN / complex membrane stability signaling
Function / homology
Function and homology information


dystrobrevin complex / olfactory nerve structural organization / sarcoglycan complex / O-linked glycosylation / establishment of blood-nerve barrier / striated muscle cell development / establishment of glial blood-brain barrier / dystroglycan complex / nerve maturation / connective tissue development ...dystrobrevin complex / olfactory nerve structural organization / sarcoglycan complex / O-linked glycosylation / establishment of blood-nerve barrier / striated muscle cell development / establishment of glial blood-brain barrier / dystroglycan complex / nerve maturation / connective tissue development / retrograde trans-synaptic signaling by trans-synaptic protein complex / walking behavior / positive regulation of basement membrane assembly involved in embryonic body morphogenesis / regulation of cellular response to growth factor stimulus / Regulation of expression of SLITs and ROBOs / regulation of skeletal muscle contraction / negative regulation of peptidyl-cysteine S-nitrosylation / contractile ring / regulation of voltage-gated calcium channel activity / regulation of gastrulation / cardiac muscle cell action potential / calcium-dependent cell-matrix adhesion / reactive oxygen species biosynthetic process / morphogenesis of an epithelial sheet / glucose import in response to insulin stimulus / nucleus localization / coronary vasculature morphogenesis / dystrophin-associated glycoprotein complex / positive regulation of sodium ion transmembrane transporter activity / microtubule anchoring / vascular associated smooth muscle cell development / laminin-1 binding / response to denervation involved in regulation of muscle adaptation / postsynaptic specialization / matrix side of mitochondrial inner membrane / Formation of the dystrophin-glycoprotein complex (DGC) / neurofilament / cell-substrate junction / myotube cell development / Striated Muscle Contraction / positive regulation of myelination / basement membrane organization / photoreceptor ribbon synapse / dystroglycan binding / regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion / heart process / lamin binding / cellular response to cholesterol / vinculin binding / regulation of epithelial to mesenchymal transition / myelination in peripheral nervous system / branching involved in salivary gland morphogenesis / skeletal muscle tissue regeneration / costamere / astrocyte projection / commissural neuron axon guidance / membrane organization / protein-containing complex localization / muscle cell development / neuron projection terminus / negative regulation of peptidyl-serine phosphorylation / node of Ranvier / cardiac muscle cell contraction / angiogenesis involved in wound healing / limb development / synaptic transmission, cholinergic / cardiac muscle cell development / axon regeneration / structural constituent of muscle / positive regulation of cell-matrix adhesion / muscle cell cellular homeostasis / nitric-oxide synthase binding / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / muscle organ development / response to muscle activity / epithelial tube branching involved in lung morphogenesis / regulation of synapse organization / alpha-actinin binding / : / membrane protein ectodomain proteolysis / basement membrane / positive regulation of oligodendrocyte differentiation / postsynaptic cytosol / regulation of ryanodine-sensitive calcium-release channel activity / plasma membrane raft / negative regulation of neuron differentiation / negative regulation of MAPK cascade / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / Schwann cell development / striated muscle contraction / response to glucose / heart morphogenesis / calcium ion homeostasis / skeletal muscle tissue development / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / cardiac muscle contraction / laminin binding / response to muscle stretch / positive regulation of neuron differentiation / tubulin binding
Similarity search - Function
Distrobrevin / Sarcoglycan complex subunit protein / Sarcoglycan alpha/epsilon / Beta-sarcoglycan / Sarcospan / Sarcoglycan gamma/delta/zeta / : / : / Sarcoglycan complex subunit protein / Sarcoglycan alpha/epsilon N-terminal domain ...Distrobrevin / 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 / Dystrophin/utrophin / EF-hand domain, type 1 / EF-hand domain, type 2 / EF hand / EF-hand / CD20-like family / CD20-like family / : / Spectrin repeat / Spectrin repeat / Spectrin/alpha-actinin / Spectrin repeats / Actinin-type actin-binding domain signature 1. / Actinin-type actin-binding domain signature 2. / Actinin-type actin-binding domain, conserved site / Cadherin-like superfamily / Calponin homology domain / Zinc finger ZZ-type signature. / Calponin homology (CH) domain / Zinc-binding domain, present in Dystrophin, CREB-binding protein. / Zinc finger, ZZ type / Zinc finger, ZZ-type / Zinc finger, ZZ-type superfamily / Zinc finger ZZ-type profile. / Calponin homology domain / CH domain superfamily / Calponin homology (CH) domain profile. / WW domain / WW/rsp5/WWP domain signature. / WW domain superfamily / WW/rsp5/WWP domain profile. / Domain with 2 conserved Trp (W) residues / WW domain / EF-hand domain pair / Immunoglobulin-like fold
Similarity search - Domain/homology
CHOLESTEROL / Chem-P5S / Dystrophin / Delta-sarcoglycan / Gamma-sarcoglycan / Beta-sarcoglycan / Alpha-sarcoglycan / Sarcospan / Dystroglycan 1 / Dystrobrevin alpha
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / Resolution: 3.5 Å
AuthorsWu, J.P. / Yan, Z. / Wan, L.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32271261 China
CitationJournal: Nature / Year: 2025
Title: Structure and assembly of the dystrophin glycoprotein complex.
Authors: Li Wan / Xiaofei Ge / Qikui Xu / Gaoxingyu Huang / Tiandi Yang / Kevin P Campbell / Zhen Yan / Jianping Wu /
Abstract: The dystrophin glycoprotein complex (DGC) has a crucial role in maintaining cell membrane stability and integrity by connecting the intracellular cytoskeleton with the surrounding extracellular ...The dystrophin glycoprotein complex (DGC) has a crucial role in maintaining cell membrane stability and integrity by connecting the intracellular cytoskeleton with the surrounding extracellular matrix. Dysfunction of dystrophin and its associated proteins results in muscular dystrophy, a disorder characterized by progressive muscle weakness and degeneration. Despite the important roles of the DGC in physiology and pathology, its structural details remain largely unknown, hindering a comprehensive understanding of its assembly and function. Here we isolated the native DGC from mouse skeletal muscle and obtained its high-resolution structure. Our findings unveil a markedly divergent structure from the previous model of DGC assembly. Specifically, on the extracellular side, β-, γ- and δ-sarcoglycans co-fold to form a specialized, extracellular tower-like structure, which has a central role in complex assembly by providing binding sites for α-sarcoglycan and dystroglycan. In the transmembrane region, sarcoglycans and sarcospan flank and stabilize the single transmembrane helix of dystroglycan, rather than forming a subcomplex as previously proposed. On the intracellular side, sarcoglycans and dystroglycan engage in assembly with the dystrophin-dystrobrevin subcomplex through extensive interaction with the ZZ domain of dystrophin. Collectively, these findings enhance our understanding of the structural linkage across the cell membrane and provide a foundation for the molecular interpretation of many muscular dystrophy-related mutations.
History
DepositionMar 25, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Dec 11, 2024Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2024Group: Data collection / Database references / Category: citation / em_admin
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Revision 1.2Dec 25, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.3Feb 12, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Alpha-sarcoglycan
B: Beta-sarcoglycan
C: Dystrobrevin alpha
D: Delta-sarcoglycan
E: Dystrophin
G: Gamma-sarcoglycan
I: unknown segment
O: Beta-dystroglycan
S: Sarcospan
hetero molecules


Theoretical massNumber of molelcules
Total (without water)241,23927
Polymers233,5639
Non-polymers7,67618
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 , 8 types, 8 molecules ABCDEGOS

#1: Protein Alpha-sarcoglycan / Alpha-SG / 50 kDa dystrophin-associated glycoprotein / 50DAG / Adhalin


Mass: 32539.186 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: P82350
#2: Protein Beta-sarcoglycan / Beta-SG / 43 kDa dystrophin-associated glycoprotein / 43DAG


Mass: 28729.967 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: P82349
#3: Protein Dystrobrevin alpha / DTN-A / Alpha-dystrobrevin


Mass: 23363.234 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q9D2N4
#4: Protein Delta-sarcoglycan / Delta-SG / 35 kDa dystrophin-associated glycoprotein / 35DAG


Mass: 29191.100 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: P82347
#5: Protein Dystrophin


Mass: 38371.391 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: P11531
#6: Protein Gamma-sarcoglycan / Gamma-SG / 35 kDa dystrophin-associated glycoprotein / 35DAG


Mass: 28956.158 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: P82348
#8: Protein Beta-dystroglycan / Beta-DG


Mass: 31934.459 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q62165
#9: Protein Sarcospan / K-ras oncogene-associated protein / Kirsten-Ras-associated protein


Mass: 19917.953 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q62147

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Protein/peptide , 1 types, 1 molecules I

#7: Protein/peptide unknown segment


Mass: 559.741 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Details: unassigned / Source: (natural) Mus musculus (house mouse)

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Sugars , 5 types, 12 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.: 5
Source method: isolated from a genetically manipulated source
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 beta-D-mannopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-3)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-3DGlcpNAcb1-3DGlcpNAcb1-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/a3-b1_b3-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(3+1)][b-D-GlcpNAc]{[(3+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#12: 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.: 2
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
#13: Polysaccharide beta-D-mannopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-3)-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.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-3DGlcpNAcb1-4DGlcpNAcb1-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_b3-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(3+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#14: 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.: 3
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
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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Non-polymers , 4 types, 6 molecules

#15: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Formula: C27H46O
#16: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: Zn
#17: Chemical ChemComp-P5S / O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine / phosphatidyl serine


Mass: 792.075 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C42H82NO10P / Feature type: SUBJECT OF INVESTIGATION
#18: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: Ca

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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-#9 / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Mus musculus (house mouse)
Buffer solutionpH: 7.4 / Details: 25 mM MOPS-Na, 150 mM NaCl, 2 mM CaCl2, 0.01% GDN
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: NO

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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: 1900 nm / Nominal defocus min: 1400 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 499658 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00316602
ELECTRON MICROSCOPYf_angle_d0.60322573
ELECTRON MICROSCOPYf_dihedral_angle_d4.5122465
ELECTRON MICROSCOPYf_chiral_restr0.0432709
ELECTRON MICROSCOPYf_plane_restr0.0042849

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