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- EMDB-36301: Cryo-EM structure of the TcsH-TMPRSS2 complex -

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Basic information

Entry
Database: EMDB / ID: EMD-36301
TitleCryo-EM structure of the TcsH-TMPRSS2 complex
Map data
Sample
  • Complex: The TcsH-TMPRSS2 complex
    • Protein or peptide: Hemorrhagic toxin
    • Protein or peptide: Transmembrane protease serine 2
  • Ligand: ZINC ION
KeywordsTcsH / TMPESS2 / TOXIN/HYDROLASE / TOXIN-HYDROLASE complex
Function / homology
Function and homology information


transmembrane protease serine 2 / host cell cytosol / glycosyltransferase activity / protein autoprocessing / Attachment and Entry / serine-type peptidase activity / host cell endosome membrane / peptidase activity / toxin activity / viral translation ...transmembrane protease serine 2 / host cell cytosol / glycosyltransferase activity / protein autoprocessing / Attachment and Entry / serine-type peptidase activity / host cell endosome membrane / peptidase activity / toxin activity / viral translation / Induction of Cell-Cell Fusion / Attachment and Entry / positive regulation of viral entry into host cell / serine-type endopeptidase activity / lipid binding / host cell plasma membrane / proteolysis / extracellular exosome / extracellular region / nucleoplasm / metal ion binding / plasma membrane
Similarity search - Function
Scavenger receptor cysteine-rich domain / SRCR domain / SRCR domain profile. / SRCR-like domain / SRCR-like domain superfamily / Scavenger receptor Cys-rich / TcdA/TcdB toxin, N-terminal helical domain / TcdB toxin N-terminal helical domain / TcdA/TcdB toxin, catalytic glycosyltransferase domain / TcdA/TcdB catalytic glycosyltransferase domain ...Scavenger receptor cysteine-rich domain / SRCR domain / SRCR domain profile. / SRCR-like domain / SRCR-like domain superfamily / Scavenger receptor Cys-rich / TcdA/TcdB toxin, N-terminal helical domain / TcdB toxin N-terminal helical domain / TcdA/TcdB toxin, catalytic glycosyltransferase domain / TcdA/TcdB catalytic glycosyltransferase domain / TcdA/TcdB toxin, pore forming domain / TcdA/TcdB pore forming domain / CGT/MARTX, cysteine protease (CPD) domain / CGT/MARTX, cysteine protease (CPD) domain superfamily / Peptidase C80 family / CGT/MARTX cysteine protease (CPD) domain profile. / Choline-binding repeat / Putative cell wall binding repeat / Cell wall/choline-binding repeat / Cell wall-binding repeat profile. / 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 / Nucleotide-diphospho-sugar transferases / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. / Serine proteases, trypsin domain profile. / Serine proteases, trypsin family, serine active site. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Hemorrhagic toxin / Transmembrane protease serine 2
Similarity search - Component
Biological speciesHomo sapiens (human) / Paeniclostridium sordellii (bacteria)
Methodsingle particle reconstruction / Resolution: 3.2 Å
AuthorsZhou R / Tao L / Zhan X
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2024
Title: Molecular basis of TMPRSS2 recognition by Paeniclostridium sordellii hemorrhagic toxin.
Authors: Ruoyu Zhou / Liuqing He / Jiahao Zhang / Xiaofeng Zhang / Yanyan Li / Xiechao Zhan / Liang Tao /
Abstract: Hemorrhagic toxin (TcsH) is a major virulence factor produced by Paeniclostridium sordellii, which is a non-negligible threat to women undergoing childbirth or abortions. Recently, Transmembrane ...Hemorrhagic toxin (TcsH) is a major virulence factor produced by Paeniclostridium sordellii, which is a non-negligible threat to women undergoing childbirth or abortions. Recently, Transmembrane Serine Protease 2 (TMPRSS2) was identified as a host receptor of TcsH. Here, we show the cryo-EM structures of the TcsH-TMPRSS2 complex and uncover that TcsH binds to the serine protease domain (SPD) of TMPRSS2 through the CROP unit-VI. This receptor binding mode is unique among LCTs. Five top surface loops of TMPRSS2, which also determine the protease substrate specificity, constitute the structural determinants recognized by TcsH. The binding of TcsH inhibits the proteolytic activity of TMPRSS2, whereas its implication in disease manifestations remains unclear. We further show that mutations selectively disrupting TMPRSS2-binding reduce TcsH toxicity in the intestinal epithelium of the female mice. These findings together shed light on the distinct molecular basis of TcsH-TMPRSS2 interactions, which expands our knowledge of host recognition mechanisms employed by LCTs and provides novel targets for developing therapeutics against P. sordellii infections.
History
DepositionMay 25, 2023-
Header (metadata) releaseMar 20, 2024-
Map releaseMar 20, 2024-
UpdateMar 20, 2024-
Current statusMar 20, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_36301.png

Downloads & links

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Map

FileDownload / File: emd_36301.map.gz / Format: CCP4 / Size: 824 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.087 Å
Density
Contour LevelBy AUTHOR: 0.35
Minimum - Maximum-2.5313616 - 5.5583887
Average (Standard dev.)0.00018422524 (±0.06504242)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions600600600
Spacing600600600
CellA=B=C: 652.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_36301_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_36301_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : The TcsH-TMPRSS2 complex

EntireName: The TcsH-TMPRSS2 complex
Components
  • Complex: The TcsH-TMPRSS2 complex
    • Protein or peptide: Hemorrhagic toxin
    • Protein or peptide: Transmembrane protease serine 2
  • Ligand: ZINC ION

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Supramolecule #1: The TcsH-TMPRSS2 complex

SupramoleculeName: The TcsH-TMPRSS2 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Hemorrhagic toxin

MacromoleculeName: Hemorrhagic toxin / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Paeniclostridium sordellii (bacteria)
Molecular weightTheoretical: 300.675219 KDa
Recombinant expressionOrganism: Bacillus subtilis (bacteria)
SequenceString: MSLISKDELI KLAYSIKPRE DEYKTILTNL DEYNKLVTIN NKDKYLQLKK LNDSIDIFIN KYKKSSRNRA LFNLKKDISK EVILIKNSN ISPVEKNLHF VWIGGEVSDT ALEYINQWAD INRDYNIRVW YDGEAFLVNT LKKAIVEHST TDTLQLFEED I KNPQFDNM ...String:
MSLISKDELI KLAYSIKPRE DEYKTILTNL DEYNKLVTIN NKDKYLQLKK LNDSIDIFIN KYKKSSRNRA LFNLKKDISK EVILIKNSN ISPVEKNLHF VWIGGEVSDT ALEYINQWAD INRDYNIRVW YDGEAFLVNT LKKAIVEHST TDTLQLFEED I KNPQFDNM KFYKKRMEFI YERQNRFINY YKSEINKPIK PTIDDIIKSH LVSEYNKNSE SLELYRRTSF EKISNNNGVD IR NNNLFTE QELLNIYNQE LLDRENLAAA SDLVRLLALK DFGGVYLDVD MLPGIQPDLF KTISRPSSIG VDSWEMIKLE AIM KYKKYI KNYTSKNFDK LDQQLKDDFQ ITLESKSEKS EIFSKLGNLD VSDLEIKIAF ALGSVINQAL ISKKGSYLTN LVIE QVKNR YKFLNQHLNP AIELGGNFSD TTKNFHDSLF NSATSENSMF LTKIASYLQV GFMPEARATI SLSGPGAYSS AYYDF INLQ DNTIEKTLNA SDLMEFKFPE SNLSQFTEQE IN(SEP)LWSFDQA SAKYQFEKYV RDYTQESLSE DSELDFNKNT VL DKNYLLN NKIPSNNVEE TGSKNYVHYI IQLQGDDISY ESACNLFSKN PKNSVIIQRN MNESAKSYFL SDNGESISEL NKY RIPQRL KNKEKIKVTF IGHGKDEFNT SEFAKLSVDS LSNEISSFLD IMKLDISPKN VEINLLGCNM FSYNVNVEET YPGK LLLNN IDKIISTLPN VNKDNITIGA NQYEVRINNE GRKELLDHSG QWLNKEEAIM NDLSSKEYIF FDSIENRPKA KSKNL IELA SISDNIKTLL LDTNIDPETK FILNNLKLNI ESSIDNNIYY EKLEPVKNII HNSIDNLTNE FNLIENVSDE LYELKK INN LDDNYLISFE DISKNDSTYT IRFINKNSGE SVHIQTEKEI FLKYGEHITQ EINTIKNNII IDVNGNLIGN IELEHAP QV NTLNAAFFIQ SLIDYSNNKD VLNNLRTSVK VQLYAQLFST GLNTIYDSIQ LVNLISNAIN DAINVLPTLT EGVPILAT I LDGISLGAAI KELSETNDPL LKKELEAKVG IIAINMSLSL ASMISTVIGV GSELAIFLLP IAGISAGIPS LVNNELILH DKATSVVNYF THLSESKKYG PFKLEDDKIL SPIDDLVISE IDFNTDSIKL GTCDILSMEG GSGYTVTNDI DHFFSSPYIN SNIPPLSIY PVMNIQTTNL DFSKDLMMLP NAPSRLLWWE TGAVPGLRSL ETDGTRLLDS IRDFYPGKFY WRFYAWFDFA I TTLKPVYE NTNIKIKLDK NTRNFIMPTI TTDVIRNNLS YSFTGSGGTY SLLLSSHPIS TNINLSKDDL WIFNIDNKVR EI SIQNGTI KKGNLVRNAL SNLDINKNKL TIDNQIINFS GDVDNKYRYI FLNCSLDDEI SLMIEINLFA KSYNLILSGN KDY LISNLS TIINKINNLG LNSKNISYNY TDEFNNKYFG VISKTNQKSI ICYKKGSKNI LELYNGNMLL FDSKDFIADD INIF MKDDI NTITGKYYID NNLDISVDFS ISLISKNKVK VNGLYLNEYG YASFLEFIKN SDGHHNTSNF INLFLDNIGF WKLFG FNNI EFVIDKYFAI TGKTDMGYIE FICDNNKNID IYFGEWKTSS TKNTIFSGNG RNLIVEPIYD INAGDNISTS IDFSYE YIS GIDIYINKIL IVPNLYTELV NINTDYSSNK YFPEIIVLNT DTFHDKVNIN LDSSSLDYEW AIDGSDFILS RYLEENN RK ILQKIRIKDI LSNTKSFNKM MIDFKDIKNI SLDHIMNNFK SFNSESELDR DHFGFKTIDS KTYYYNEVGK LVKGSINI N DSLFYFDTIE SNLVTGWKTI NGKTYYFDIN NGVAYIGYKT IDGKNFYFDG NGIMQIGVFK VPDGFKYFAP ANTYNNNEE GQTIVYQNKF LTINGKKYYF DNNSKAVTGW QIINGNKYYF DTNTGIAAVG LQIINNNKYY FNPHTAIAAT GWQSINNAKY YFDINTYIG TTGYKTIDSK NFYFDSNCIM QIGVFKVSDG FKYFAPANTY NNNEEGQAIV YQNKFLTING KRYYFDNNSK A VTGWHTID GKKYYFNPNT AIAATGWHTI DDKKYYFNPD TAIAATGWHT IDDKKYYFNP NTGITSTGET TINNKSFYFN DK GIMQIGV FKVPDGFKYF APANTHNNNL EGQAIVYQNK FLTINGKKYY FDNNSKAITG WQVIDDKKYY FNSNTAVADT NLC TINNEK YYFSYDGILQ NGYITIGRLN FYFDSNNDSK MTTGVFKGPN GFEYFAPANT YNNNLEGQAI VYQNKFLTIN GKKY YFDNK SKAVTGWQTI DGKKYYFNPN TAIAAMGWQA IDGKKYYFNP NTAIATTGWQ TIDGKKYYFN PNTAIAATGW QAIDG KKYY FNPNTATTSI GYTTINSKNF YFNNDGIMQL GVFKGPDGFE YFAPANTHNN NEEGQSITYQ NKFLIFNEDV YYFDSS SKA VTGWRTIDDH RFYFEPNTGI GANGYKTLDG KNFYFRNGLP QFGVFKGPDG FEYFAPANTH NNNEEGQSIT YQNKFLV FL GNRYYFDSSS KAVTGWQTIN GNTYYFMPDT AIAAAGGFFT IDGAIYFFGI DGVKQPGIYG HHHHHHHH

UniProtKB: Hemorrhagic toxin

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Macromolecule #2: Transmembrane protease serine 2

MacromoleculeName: Transmembrane protease serine 2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: transmembrane protease serine 2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 46.712984 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGILPSPGMP ALLSLVSLLS VLLMGCVAET GHHHHHHWKF MGSKCSNSGI ECDSSGTCIN PSNWCDGVSH CPGGEDENRC VRLYGPNFI LQVYSSQRKS WHPVCQDDWN ENYGRAACRD MGYKNNFYSS QGIVDDSGST SFMKLNTSAG NVDIYKKLYH S DACSSKAV ...String:
MGILPSPGMP ALLSLVSLLS VLLMGCVAET GHHHHHHWKF MGSKCSNSGI ECDSSGTCIN PSNWCDGVSH CPGGEDENRC VRLYGPNFI LQVYSSQRKS WHPVCQDDWN ENYGRAACRD MGYKNNFYSS QGIVDDSGST SFMKLNTSAG NVDIYKKLYH S DACSSKAV VSLRCIACGV NLNSSRQSQI VGGESALPGA WPWQVSLHVQ NVHVCGGSII TPEWIVTAAH CVEKPLNNPW HW TAFAGIL RQSFMFYGAG YQVEKVISHP NYDSKTKNND IALMKLQKPL TFNDLVKPVC LPNPGMMLQP EQLCWISGWG ATE EKGKTS EVLNAAKVLL IETQRCNSRY VYDNLITPAM ICAGFLQGNV DSCQGDSGGP LVTSKNNIWW LIGDTSWGSG CAKA YRPGV YGNVMVFTDW IYRQMRADG

UniProtKB: Transmembrane protease serine 2

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Macromolecule #3: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 3 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Experimental details

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Structure determination

Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.5 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 87378
FSC plot (resolution estimation)

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