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- PDB-7m0r: Cryo-EM structure of the Sema3A/PlexinA4/Neuropilin 1 complex -

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Basic information

Entry
Database: PDB / ID: 7m0r
TitleCryo-EM structure of the Sema3A/PlexinA4/Neuropilin 1 complex
Components
  • Neuropilin-1
  • Plexin-A4
  • Semaphorin-3A
KeywordsSIGNALING PROTEIN / plexin / semaphorin / neuropilin / signaling
Function / homology
Function and homology information


Neurophilin interactions with VEGF and VEGFR / neural crest cell migration involved in sympathetic nervous system development / glossopharyngeal nerve morphogenesis / chemorepulsion of branchiomotor axon / regulation of negative chemotaxis / vagus nerve morphogenesis / cell migration involved in coronary vasculogenesis / cranial nerve morphogenesis / trigeminal nerve morphogenesis / Signal transduction by L1 ...Neurophilin interactions with VEGF and VEGFR / neural crest cell migration involved in sympathetic nervous system development / glossopharyngeal nerve morphogenesis / chemorepulsion of branchiomotor axon / regulation of negative chemotaxis / vagus nerve morphogenesis / cell migration involved in coronary vasculogenesis / cranial nerve morphogenesis / trigeminal nerve morphogenesis / Signal transduction by L1 / anterior commissure morphogenesis / regulation of axon extension involved in axon guidance / postganglionic parasympathetic fiber development / facial nerve morphogenesis / basal dendrite development / otic placode development / CRMPs in Sema3A signaling / protein localization to early endosome / Sema3A PAK dependent Axon repulsion / basal dendrite arborization / dichotomous subdivision of terminal units involved in salivary gland branching / positive regulation of smooth muscle cell chemotaxis / sympathetic neuron axon guidance / retina vasculature morphogenesis in camera-type eye / vestibulocochlear nerve structural organization / dorsal root ganglion morphogenesis / ventral trunk neural crest cell migration / sympathetic neuron projection guidance / facioacoustic ganglion development / trigeminal ganglion development / trigeminal nerve structural organization / sensory neuron axon guidance / postsynapse organization / epithelial cell migration / facial nerve structural organization / gonadotrophin-releasing hormone neuronal migration to the hypothalamus / branchiomotor neuron axon guidance / semaphorin receptor binding / positive regulation of male gonad development / negative regulation of axon extension involved in axon guidance / axon extension involved in axon guidance / renal artery morphogenesis / VEGF-activated neuropilin signaling pathway / blood vessel endothelial cell migration / neurofilament / SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion / cerebellar climbing fiber to Purkinje cell synapse / maintenance of synapse structure / sympathetic neuron projection extension / synaptic target recognition / vascular endothelial growth factor binding / negative regulation of epithelial cell migration / angiogenesis involved in coronary vascular morphogenesis / motor neuron migration / neural crest cell migration involved in autonomic nervous system development / sympathetic ganglion development / retina vasculature development in camera-type eye / negative regulation of axon extension / positive regulation of axon extension involved in axon guidance / axonogenesis involved in innervation / vascular endothelial growth factor receptor activity / endothelial cell chemotaxis / nerve development / positive regulation of neuron migration / neuropilin signaling pathway / neuropilin binding / sympathetic nervous system development / olfactory bulb development / substrate-dependent cell migration, cell extension / positive regulation of platelet-derived growth factor receptor signaling pathway / hepatocyte growth factor receptor signaling pathway / coronary artery morphogenesis / semaphorin receptor activity / chemorepellent activity / commissural neuron axon guidance / outflow tract septum morphogenesis / embryonic heart tube development / motor neuron axon guidance / positive regulation of vascular associated smooth muscle cell migration / axonal fasciculation / retinal ganglion cell axon guidance / sprouting angiogenesis / axon extension / cell migration involved in sprouting angiogenesis / regulation of Cdc42 protein signal transduction / positive regulation of cell migration involved in sprouting angiogenesis / positive regulation of filopodium assembly / artery morphogenesis / negative chemotaxis / cellular response to hepatocyte growth factor stimulus / growth factor binding / branching involved in blood vessel morphogenesis / dendrite morphogenesis / positive chemotaxis / sorting endosome / platelet-derived growth factor receptor signaling pathway / dendrite development / semaphorin-plexin signaling pathway / positive regulation of phosphorylation / cellular response to vascular endothelial growth factor stimulus
Similarity search - Function
Semaphorin-3A, sema domain / IL-1Ra-like, immunoglobulin domain / Immunoglobulin domain / Semaphorin / Spermadhesin, CUB domain / Plexin, TIG domain 2 / TIG domain found in plexin / Plexin A/B, PSI domain / Plexin, TIG domain 1 / TIG domain ...Semaphorin-3A, sema domain / IL-1Ra-like, immunoglobulin domain / Immunoglobulin domain / Semaphorin / Spermadhesin, CUB domain / Plexin, TIG domain 2 / TIG domain found in plexin / Plexin A/B, PSI domain / Plexin, TIG domain 1 / TIG domain / Neuropilin / Neuropilin, C-terminal / C-terminal domain of neuropilin glycoprotein / Plexin, cytoplasmic RasGAP domain / Plexin, cytoplasmic RhoGTPase-binding domain / Plexin cytoplasmic RasGAP domain / Plexin cytoplasmic RhoGTPase-binding domain / MAM domain signature. / Domain in meprin, A5, receptor protein tyrosine phosphatase mu (and others) / : / Plexin family / Coagulation factors 5/8 type C domain (FA58C) signature 2. / MAM domain, meprin/A5/mu / MAM domain / MAM domain profile. / Plexin repeat / Plexin repeat / Coagulation factors 5/8 type C domain (FA58C) signature 1. / Sema domain / semaphorin domain / Sema domain / Sema domain superfamily / Sema domain profile. / CUB domain / Domain first found in C1r, C1s, uEGF, and bone morphogenetic protein. / CUB domain / CUB domain profile. / Spermadhesin, CUB domain superfamily / Coagulation factor 5/8 C-terminal domain, discoidin domain / IPT/TIG domain / Coagulation factors 5/8 type C domain (FA58C) profile. / ig-like, plexins, transcription factors / Rho GTPase activation protein / F5/8 type C domain / Coagulation factor 5/8 C-terminal domain / IPT domain / PSI domain / domain found in Plexins, Semaphorins and Integrins / Galactose-binding domain-like / Galactose-binding-like domain superfamily / Immunoglobulin subtype / Immunoglobulin / Immunoglobulin E-set / Concanavalin A-like lectin/glucanase domain superfamily / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Jelly Rolls / WD40/YVTN repeat-like-containing domain superfamily / Immunoglobulin-like fold / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Semaphorin-3A / Neuropilin-1 / Plexin-A4
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsLu, D. / Shang, G. / He, X. / Bai, X. / Zhang, X.
Funding support United States, 5items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM130289 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM136976 United States
Robert A. Welch FoundationI-1702 United States
Robert A. Welch FoundationI-1944 United States
Cancer Prevention and Research Institute of Texas (CPRIT)RP160082 United States
CitationJournal: Nat Commun / Year: 2021
Title: Architecture of the Sema3A/PlexinA4/Neuropilin tripartite complex.
Authors: Defen Lu / Guijun Shang / Xiaojing He / Xiao-Chen Bai / Xuewu Zhang /
Abstract: Secreted class 3 semaphorins (Sema3s) form tripartite complexes with the plexin receptor and neuropilin coreceptor, which are both transmembrane proteins that together mediate semaphorin signal for ...Secreted class 3 semaphorins (Sema3s) form tripartite complexes with the plexin receptor and neuropilin coreceptor, which are both transmembrane proteins that together mediate semaphorin signal for neuronal axon guidance and other processes. Despite extensive investigations, the overall architecture of and the molecular interactions in the Sema3/plexin/neuropilin complex are incompletely understood. Here we present the cryo-EM structure of a near intact extracellular region complex of Sema3A, PlexinA4 and Neuropilin 1 (Nrp1) at 3.7 Å resolution. The structure shows a large symmetric 2:2:2 assembly in which each subunit makes multiple interactions with others. The two PlexinA4 molecules in the complex do not interact directly, but their membrane proximal regions are close to each other and poised to promote the formation of the intracellular active dimer for signaling. The structure reveals a previously unknown interface between the a2b1b2 module in Nrp1 and the Sema domain of Sema3A. This interaction places the a2b1b2 module at the top of the complex, far away from the plasma membrane where the transmembrane regions of Nrp1 and PlexinA4 embed. As a result, the region following the a2b1b2 module in Nrp1 must span a large distance to allow the connection to the transmembrane region, suggesting an essential role for the long non-conserved linkers and the MAM domain in neuropilin in the semaphorin/plexin/neuropilin complex.
History
DepositionMar 11, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 5, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 9, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Oct 16, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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Assembly

Deposited unit
E: Neuropilin-1
C: Semaphorin-3A
F: Neuropilin-1
D: Semaphorin-3A
A: Plexin-A4
B: Plexin-A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)530,79510
Polymers530,6346
Non-polymers1604
Water00
1


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

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Components

#1: Protein Neuropilin-1 / A5 protein


Mass: 64132.211 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Nrp1, Nrp / Production host: Homo sapiens (human) / References: UniProt: P97333
#2: Protein Semaphorin-3A / Semaphorin III / Sema III / Semaphorin-D / Sema D


Mass: 67931.812 Da / Num. of mol.: 2 / Mutation: A106K,551ARTRA555,731AAQAA735,758ANRA761
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Sema3a, Semad, SemD / Production host: Homo sapiens (human) / References: UniProt: O08665
#3: Antibody Plexin-A4


Mass: 133253.203 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Plxna4, Kiaa1550 / Production host: Homo sapiens (human) / References: UniProt: Q80UG2
#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca
Has ligand of interestN
Has protein modificationY
Sequence detailsThe full sequence of Semaphorin-3A is NYANGKNNVPRLKLSYKEMLESNNVITFNGLANSSSYHTFLLDEERSRLYVGAKDHIFSF ...The full sequence of Semaphorin-3A is NYANGKNNVPRLKLSYKEMLESNNVITFNGLANSSSYHTFLLDEERSRLYVGAKDHIFSF NLVNIKDFQKIVWPVSYTRRDECKWKGKDILKECANFIKVLEAYNQTHLYACGTGAFHPI CTYIEVGHHPEDNIFKLQDSHFENGRGKSPYDPKLLTASLLIDGELYSGTAADFMGRDFA IFRTLGHHHPIRTEQHDSRWLNDPRFISAHLIPESDNPEDDKVYFFFRENAIDGEHSGKA THARIGQICKNDFGGHRSLVNKWTTFLKARLICSVPGPNGIDTHFDELQDVFLMNSKDPK NPIVYGVFTTSSNIFKGSAVCMYSMSDVRRVFLGPYAHRDGPNYQWVPYQGRVPYPRPGT CPSKTFGGFDSTKDLPDDVITFARSHPAMYNPVFPINNRPIMIKTDVNYQFTQIVVDRVD AEDGQYDVMFIGTDVGTVLKVVSVPKETWHDLEEVLLEEMTVFREPTTISAMELSTKQQQ LYIGSTAGVAQLPLHRCDIYGKACAECCLARDPYCAWDGSSCSRYFPTAKARTRAQDIRN GDPLTHCSDLQHHDNHHGPSLEERIIYGVENSSTFLECSPKSQRALVYWQFQRRNEDRKE EIRMGDHIIRTEQGLLLRSLQKKDSGNYLCHAVEHGFMQTLLKVTLEVIDTEHLEELLHK DDDGDGSKIKEMSSSMTPSQKVWYRDFMQLINHPNLNTMDEFCEQVWKRDAAQAAQRPGH SQGSSNKWKHMQESKKGANRATHEFERAPR

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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: Ternary complex of Sema3A, PlexinA4 and neuropilin 1 / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 600 kDa/nm / Experimental value: YES
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
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 FIELD / Cs: 2.7 mm / C2 aperture diameter: 100 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1RELION3.1particle selection
2SerialEMimage acquisition
4Gctf1.06CTF correction
10RELIONinitial Euler assignment
11RELIONfinal Euler assignment
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1453090
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 26741 / Symmetry type: POINT

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