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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-1Neuropilin 1
  • Plexin-A4
  • Semaphorin-3ASemaphorin
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 / anterior commissure morphogenesis / cranial nerve morphogenesis / trigeminal nerve morphogenesis ...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 / anterior commissure morphogenesis / cranial nerve morphogenesis / trigeminal nerve morphogenesis / Signal transduction by L1 / regulation of axon extension involved in axon guidance / postganglionic parasympathetic fiber development / synaptic target recognition / facial nerve morphogenesis / sympathetic neuron axon guidance / CRMPs in Sema3A signaling / basal dendrite development / protein localization to early endosome / otic placode development / neurofilament / basal dendrite arborization / Sema3A PAK dependent Axon repulsion / dichotomous subdivision of terminal units involved in salivary gland branching / retina vasculature morphogenesis in camera-type eye / regulation of vascular endothelial growth factor receptor signaling pathway / vestibulocochlear nerve structural organization / semaphorin receptor binding / dorsal root ganglion morphogenesis / epithelial cell migration / ventral trunk neural crest cell migration / sympathetic neuron projection guidance / facioacoustic ganglion development / trigeminal ganglion development / cerebellar climbing fiber to Purkinje cell synapse / trigeminal nerve structural organization / sensory neuron axon guidance / facial nerve structural organization / gonadotrophin-releasing hormone neuronal migration to the hypothalamus / postsynapse organization / branchiomotor neuron axon guidance / renal artery morphogenesis / positive regulation of male gonad development / SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion / semaphorin-plexin signaling pathway involved in axon guidance / maintenance of synapse structure / axon extension involved in axon guidance / VEGF-activated neuropilin signaling pathway / negative regulation of axon extension involved in axon guidance / retina vasculature development in camera-type eye / blood vessel endothelial cell migration / sympathetic neuron projection extension / negative regulation of epithelial cell migration / motor neuron migration / endothelial cell chemotaxis / vascular endothelial growth factor binding / sympathetic ganglion development / axonogenesis involved in innervation / neural crest cell migration involved in autonomic nervous system development / positive regulation of axon extension involved in axon guidance / negative regulation of axon extension / vascular endothelial growth factor receptor activity / substrate-dependent cell migration, cell extension / nerve development / semaphorin receptor complex / positive regulation of neuron migration / angiogenesis involved in coronary vascular morphogenesis / olfactory bulb development / sympathetic nervous system development / hepatocyte growth factor receptor signaling pathway / neuropilin signaling pathway / neuropilin binding / coronary artery morphogenesis / outflow tract septum morphogenesis / regulation of Cdc42 protein signal transduction / chemorepellent activity / semaphorin receptor activity / commissural neuron axon guidance / embryonic heart tube development / negative regulation of cell adhesion / axon extension / motor neuron axon guidance / cell migration involved in sprouting angiogenesis / retinal ganglion cell axon guidance / artery morphogenesis / axonal fasciculation / dendrite morphogenesis / sprouting angiogenesis / neural crest cell migration / positive regulation of filopodium assembly / negative chemotaxis / branching involved in blood vessel morphogenesis / cellular response to hepatocyte growth factor stimulus / positive regulation of axonogenesis / positive regulation of cell migration involved in sprouting angiogenesis / positive chemotaxis / dendrite development / growth factor binding / sorting endosome / positive regulation of focal adhesion assembly
Similarity search - Function
Semaphorin-3A, sema domain / IL-1Ra-like, immunoglobulin domain / Immunoglobulin domain / Semaphorin / Plexin, TIG domain 2 / TIG domain found in plexin / Plexin, TIG domain 1 / TIG domain / Neuropilin / Neuropilin, C-terminal ...Semaphorin-3A, sema domain / IL-1Ra-like, immunoglobulin domain / Immunoglobulin domain / Semaphorin / Plexin, TIG domain 2 / TIG domain found in plexin / Plexin, TIG domain 1 / TIG domain / Neuropilin / Neuropilin, C-terminal / Plexin, cytoplasmic RhoGTPase-binding domain / C-terminal domain of neuropilin glycoprotein / Plexin cytoplasmic RhoGTPase-binding domain / Plexin, cytoplasmic RasGAP domain / Plexin cytoplasmic RasGAP domain / MAM domain signature. / Domain in meprin, A5, receptor protein tyrosine phosphatase mu (and others) / MAM domain, meprin/A5/mu / MAM domain / Coagulation factors 5/8 type C domain (FA58C) signature 2. / MAM domain profile. / Plexin family / CUB domain / Domain first found in C1r, C1s, uEGF, and bone morphogenetic protein. / CUB domain / CUB domain profile. / Coagulation factors 5/8 type C domain (FA58C) signature 1. / Plexin repeat / Plexin repeat / Spermadhesin, CUB domain superfamily / Sema domain / semaphorin domain / Sema domain / Sema domain superfamily / Sema domain profile. / 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 / F5/8 type C domain / Rho GTPase activation protein / PSI domain / domain found in Plexins, Semaphorins and Integrins / Coagulation factor 5/8 C-terminal domain / IPT domain / Galactose-binding-like domain superfamily / Immunoglobulin E-set / Concanavalin A-like lectin/glucanase domain superfamily / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Immunoglobulin-like fold
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

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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
Water0
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 / 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 / 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: Protein 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
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 FIELDBright-field microscopy / 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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