[English] 日本語

- EMDB-45165: Cryo-EM structure of native dystrophin-glycoprotein complex (DGC) -
+
Open data
-
Basic information
Entry | ![]() | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Title | Cryo-EM structure of native dystrophin-glycoprotein complex (DGC) | |||||||||
![]() | ||||||||||
![]() |
| |||||||||
![]() | beta-helix / sarcolemma / glycosylation / muscular dystrophy / membrane protein | |||||||||
Function / homology | ![]() sarcoglycan complex / coronary vasculature morphogenesis / muscle attachment / dystroglycan complex / nerve maturation / retrograde trans-synaptic signaling by trans-synaptic protein complex / contractile ring / morphogenesis of an epithelial sheet / microtubule anchoring / dystrophin-associated glycoprotein complex ...sarcoglycan complex / coronary vasculature morphogenesis / muscle attachment / dystroglycan complex / nerve maturation / retrograde trans-synaptic signaling by trans-synaptic protein complex / contractile ring / morphogenesis of an epithelial sheet / microtubule anchoring / dystrophin-associated glycoprotein complex / laminin-1 binding / photoreceptor ribbon synapse / basement membrane organization / dystroglycan binding / vinculin binding / branching involved in salivary gland morphogenesis / myelination in peripheral nervous system / commissural neuron axon guidance / protein-containing complex localization / node of Ranvier / cardiac muscle cell contraction / cardiac muscle cell development / cardiac muscle tissue development / structural constituent of muscle / muscle organ development / regulation of synapse organization / heart contraction / epithelial tube branching involved in lung morphogenesis / response to muscle activity / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / alpha-actinin binding / membrane protein ectodomain proteolysis / basement membrane / heart morphogenesis / calcium ion homeostasis / negative regulation of MAPK cascade / tubulin binding / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / SH2 domain binding / negative regulation of cell migration / sarcoplasmic reticulum / filopodium / calcium-mediated signaling / sarcolemma / GABA-ergic synapse / regulation of synaptic plasticity / cell-cell junction / protein transport / 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 | |||||||||
Biological species | ![]() ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 4.3 Å | |||||||||
![]() | Liu S / Su T / Xia X / Zhou ZH | |||||||||
Funding support | ![]()
| |||||||||
![]() | ![]() 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 |
|
-
Structure visualization
Supplemental images |
---|
-
Downloads & links
-EMDB archive
Map data | ![]() | 168.3 MB | ![]() | |
---|---|---|---|---|
Header (meta data) | ![]() ![]() | 28.7 KB 28.7 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 11.9 KB | Display | ![]() |
Images | ![]() | 73.5 KB | ||
Filedesc metadata | ![]() | 10.9 KB | ||
Others | ![]() ![]() | 165.4 MB 165.4 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 734.1 KB | Display | ![]() |
---|---|---|---|---|
Full document | ![]() | 733.7 KB | Display | |
Data in XML | ![]() | 20.3 KB | Display | |
Data in CIF | ![]() | 26.6 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 9c3cMC M: atomic model generated by this map C: citing same article ( |
---|---|
Similar structure data | Similarity search - Function & homology ![]() |
-
Links
EMDB pages | ![]() ![]() |
---|---|
Related items in Molecule of the Month |
-
Map
File | ![]() | ||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.36 Å | ||||||||||||||||||||||||||||||||||||
Density |
| ||||||||||||||||||||||||||||||||||||
Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
|
-Supplemental data
-Half map: #1
File | emd_45165_half_map_1.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Projections & Slices |
| ||||||||||||
Density Histograms |
-Half map: #2
File | emd_45165_half_map_2.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Projections & Slices |
| ||||||||||||
Density Histograms |
-
Sample components
+Entire : dystrophin-glycoprotein complex (DGC)
+Supramolecule #1: dystrophin-glycoprotein complex (DGC)
+Macromolecule #1: Alpha-dystroglycan
+Macromolecule #2: Beta-dystroglycan
+Macromolecule #3: Dystrophin
+Macromolecule #4: Alpha-sarcoglycan
+Macromolecule #5: Beta-sarcoglycan
+Macromolecule #6: Sarcoglycan delta
+Macromolecule #7: Gamma-sarcoglycan
+Macromolecule #8: Sarcospan
+Macromolecule #9: Dystrobrevin
+Macromolecule #12: 2-acetamido-2-deoxy-beta-D-glucopyranose
-Experimental details
-Structure determination
Method | cryo EM |
---|---|
![]() | single particle reconstruction |
Aggregation state | particle |
-
Sample preparation
Buffer | pH: 7.4 Details: 150 mM NaCl, 0.1% digitonin, 50 mM Tris-HCl, pH 7.4 |
---|---|
Grid | Model: PELCO Ultrathin Carbon with Lacey Carbon / Material: COPPER / Mesh: 400 / Support film - Material: CARBON / Support film - topology: LACEY / Pretreatment - Type: GLOW DISCHARGE |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 281.15 K / Instrument: FEI VITROBOT MARK IV |
-
Electron microscopy
Microscope | FEI TITAN KRIOS |
---|---|
Specialist optics | Energy filter - Name: GIF Quantum LS / Energy filter - Slit width: 20 eV |
Image recording | #0 - Image recording ID: 1 / #0 - Film or detector model: GATAN K2 SUMMIT (4k x 4k) / #0 - Detector mode: SUPER-RESOLUTION / #0 - Average electron dose: 50.0 e/Å2 / #1 - Image recording ID: 2 / #1 - Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / #1 - Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | C2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.5 µm |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
+
Image processing
-Atomic model buiding 1
Refinement | Space: REAL |
---|---|
Output model | ![]() PDB-9c3c: |