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- PDB-8s9p: 1:1:1 agrin/LRP4/MuSK complex -

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Basic information

Entry
Database: PDB / ID: 8s9p
Title1:1:1 agrin/LRP4/MuSK complex
Components
  • Agrin
  • Low-density lipoprotein receptor-related protein 4
  • Muscle, skeletal receptor tyrosine-protein kinaseSkeletal muscle
KeywordsSIGNALING PROTEIN / agrin / LRP4 / MuSK / NMJ / RTK
Function / homology
Function and homology information


positive regulation of presynaptic membrane organization / positive regulation of protein geranylgeranylation / Defective B3GALT6 causes EDSP2 and SEMDJL1 / Defective B4GALT7 causes EDS, progeroid type / Defective B3GAT3 causes JDSSDHD / regulation of synaptic assembly at neuromuscular junction / Defective EXT2 causes exostoses 2 / Defective EXT1 causes exostoses 1, TRPS2 and CHDS / : / clustering of voltage-gated sodium channels ...positive regulation of presynaptic membrane organization / positive regulation of protein geranylgeranylation / Defective B3GALT6 causes EDSP2 and SEMDJL1 / Defective B4GALT7 causes EDS, progeroid type / Defective B3GAT3 causes JDSSDHD / regulation of synaptic assembly at neuromuscular junction / Defective EXT2 causes exostoses 2 / Defective EXT1 causes exostoses 1, TRPS2 and CHDS / : / clustering of voltage-gated sodium channels / positive regulation of synaptic assembly at neuromuscular junction / postsynaptic membrane assembly / A tetrasaccharide linker sequence is required for GAG synthesis / skeletal muscle acetylcholine-gated channel clustering / chondroitin sulfate binding / presynaptic membrane assembly / HS-GAG biosynthesis / HS-GAG degradation / sialic acid binding / negative regulation of axonogenesis / proximal/distal pattern formation / positive regulation of skeletal muscle acetylcholine-gated channel clustering / dystroglycan binding / Wnt-protein binding / amyloid-beta clearance by cellular catabolic process / heparan sulfate proteoglycan binding / NCAM1 interactions / negative regulation of ossification / synaptic assembly at neuromuscular junction / dorsal/ventral pattern formation / positive regulation of kinase activity / dendrite morphogenesis / limb development / positive regulation of filopodium assembly / generation of neurons / embryonic digit morphogenesis / neuromuscular junction development / receptor clustering / odontogenesis of dentin-containing tooth / plasma membrane raft / apolipoprotein binding / Non-integrin membrane-ECM interactions / basement membrane / hair follicle development / ECM proteoglycans / laminin binding / Integrin cell surface interactions / Retinoid metabolism and transport / transmembrane receptor protein tyrosine kinase activity / lysosomal lumen / synaptic membrane / kidney development / synapse organization / negative regulation of canonical Wnt signaling pathway / neuromuscular junction / G protein-coupled acetylcholine receptor signaling pathway / structural constituent of cytoskeleton / positive regulation of neuron projection development / receptor tyrosine kinase binding / receptor protein-tyrosine kinase / memory / Wnt signaling pathway / positive regulation of GTPase activity / Golgi lumen / endocytosis / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of peptidyl-tyrosine phosphorylation / postsynaptic membrane / scaffold protein binding / collagen-containing extracellular matrix / protein tyrosine kinase activity / Attachment and Entry / postsynaptic density / protein autophosphorylation / cell differentiation / receptor complex / positive regulation of protein phosphorylation / dendrite / neuronal cell body / synapse / calcium ion binding / positive regulation of gene expression / cell surface / signal transduction / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / extracellular exosome / extracellular region / ATP binding / metal ion binding / plasma membrane
Similarity search - Function
NtA (N-terminal agrin) domain / Agrin NtA domain / NtA (N-terminal agrin) domain profile. / Follistatin-like, N-terminal / Follistatin-N-terminal domain-like / Factor I / membrane attack complex / factor I membrane attack complex / Complement Clr-like EGF domain / Domain found in sea urchin sperm protein, enterokinase, agrin / Laminin-type EGF-like (LE) domain profile. ...NtA (N-terminal agrin) domain / Agrin NtA domain / NtA (N-terminal agrin) domain profile. / Follistatin-like, N-terminal / Follistatin-N-terminal domain-like / Factor I / membrane attack complex / factor I membrane attack complex / Complement Clr-like EGF domain / Domain found in sea urchin sperm protein, enterokinase, agrin / Laminin-type EGF-like (LE) domain profile. / Laminin G domain / Laminin-type EGF-like (LE) domain signature. / Laminin-type epidermal growth factor-like domai / Laminin EGF domain / Complement Clr-like EGF-like / Kazal-type serine protease inhibitor domain / SEA domain superfamily / Laminin-type EGF domain / SEA domain profile. / Kazal-type serine protease inhibitor domain / SEA domain / SEA domain / Frizzled domain / Frizzled cysteine-rich domain superfamily / Fz domain / Frizzled (fz) domain profile. / Low-density lipoprotein receptor repeat class B / LDL-receptor class B (LDLRB) repeat profile. / Laminin G domain profile. / LDLR class B repeat / Low-density lipoprotein-receptor YWTD domain / Kazal type serine protease inhibitors / Laminin G domain / Laminin G domain / Kazal domain superfamily / Kazal domain / Kazal domain profile. / Tissue inhibitor of metalloproteinases-like, OB-fold / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A, conserved site / LDL-receptor class A (LDLRA) domain signature. / LDL-receptor class A (LDLRA) domain profile. / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat / LDL receptor-like superfamily / Six-bladed beta-propeller, TolB-like / Coagulation Factor Xa inhibitory site / EGF-like domain / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / Immunoglobulin domain / Aspartic acid and asparagine hydroxylation site. / EGF-like calcium-binding domain / Calcium-binding EGF-like domain / Immunoglobulin I-set / Immunoglobulin I-set domain / Epidermal growth factor-like domain. / EGF-like domain profile. / Growth factor receptor cysteine-rich domain superfamily / EGF-like domain signature 2. / EGF-like domain signature 1. / EGF-like domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Concanavalin A-like lectin/glucanase domain superfamily / Tyrosine protein kinases specific active-site signature. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Agrin / Muscle, skeletal receptor tyrosine-protein kinase / Low-density lipoprotein receptor-related protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsXie, T. / Xu, G.J. / Liu, Y. / Quade, B. / Lin, W.C. / Bai, X.C.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM143158 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2023
Title: Structural insights into the assembly of the agrin/LRP4/MuSK signaling complex.
Authors: Tian Xie / Guangjun Xu / Yun Liu / Bradley Quade / Weichun Lin / Xiao-Chen Bai /
Abstract: MuSK is a receptor tyrosine kinase (RTK) that plays essential roles in the formation and maintenance of the neuromuscular junction. Distinct from most members of RTK family, MuSK activation requires ...MuSK is a receptor tyrosine kinase (RTK) that plays essential roles in the formation and maintenance of the neuromuscular junction. Distinct from most members of RTK family, MuSK activation requires not only its cognate ligand agrin but also its coreceptors LRP4. However, how agrin and LRP4 coactivate MuSK remains unclear. Here, we report the cryo-EM structure of the extracellular ternary complex of agrin/LRP4/MuSK in a stoichiometry of 1:1:1. This structure reveals that arc-shaped LRP4 simultaneously recruits both agrin and MuSK to its central cavity, thereby promoting a direct interaction between agrin and MuSK. Our cryo-EM analyses therefore uncover the assembly mechanism of agrin/LRP4/MuSK signaling complex and reveal how MuSK receptor is activated by concurrent binding of agrin and LRP4.
History
DepositionMar 29, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 17, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 14, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Agrin
B: Low-density lipoprotein receptor-related protein 4
C: Muscle, skeletal receptor tyrosine-protein kinase


Theoretical massNumber of molelcules
Total (without water)527,0043
Polymers527,0043
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Agrin /


Mass: 217553.922 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AGRN, AGRIN / Production host: Homo sapiens (human) / References: UniProt: O00468
#2: Protein Low-density lipoprotein receptor-related protein 4 / LRP-4 / Multiple epidermal growth factor-like domains 7


Mass: 212287.031 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LRP4, KIAA0816, LRP10, MEGF7 / Production host: Homo sapiens (human) / References: UniProt: O75096
#3: Protein Muscle, skeletal receptor tyrosine-protein kinase / Skeletal muscle / Muscle-specific tyrosine-protein kinase receptor / MuSK / Muscle-specific kinase receptor


Mass: 97163.227 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MUSK / Production host: Homo sapiens (human)
References: UniProt: O15146, receptor protein-tyrosine kinase

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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: 1:1:1 agrin/LRP4/MuSK complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4 / Details: 25 mM HEPES pH 7.4, 150 mM NaCl, and 2 mM CaCl2
SpecimenConc.: 0.56 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 %

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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 / Nominal defocus max: 2600 nm / Nominal defocus min: 1600 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

EM software
IDNameCategory
1RELIONparticle selection
2SerialEMimage acquisition
4GctfCTF correction
10RELIONinitial Euler assignment
11RELIONfinal Euler assignment
12RELIONclassification
13RELION3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2414116
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 82511 / Symmetry type: POINT

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