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- EMDB-36303: Cryo-EM structure of the TcsH-CROP in complex with TMPRSS2 -

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Basic information

Entry
Database: EMDB / ID: EMD-36303
TitleCryo-EM structure of the TcsH-CROP in complex with TMPRSS2
Map data
Sample
  • Complex: The TcsH-TMPRSS2 complex
    • Protein or peptide: Transmembrane protease serine 2
    • Protein or peptide: Maltose/maltodextrin-binding periplasmic protein,Hemorrhagic toxin
KeywordsTcsH / TMPESS2 / TOXIN/HYDROLASE / TOXIN-HYDROLASE complex
Function / homology
Function and homology information


transmembrane protease serine 2 / host cell cytosol / detection of maltose stimulus / maltose transport complex / glycosyltransferase activity / maltose binding / carbohydrate transport / maltose transport / maltodextrin transmembrane transport / protein autoprocessing ...transmembrane protease serine 2 / host cell cytosol / detection of maltose stimulus / maltose transport complex / glycosyltransferase activity / maltose binding / carbohydrate transport / maltose transport / maltodextrin transmembrane transport / protein autoprocessing / carbohydrate transmembrane transporter activity / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / cysteine-type peptidase activity / Attachment and Entry / serine-type peptidase activity / ATP-binding cassette (ABC) transporter complex / cell chemotaxis / host cell endosome membrane / outer membrane-bounded periplasmic space / toxin activity / viral translation / Induction of Cell-Cell Fusion / periplasmic space / Attachment and Entry / positive regulation of viral entry into host cell / serine-type endopeptidase activity / lipid binding / DNA damage response / host cell plasma membrane / proteolysis / extracellular exosome / extracellular region / nucleoplasm / membrane / metal ion binding / plasma membrane
Similarity search - Function
Scavenger receptor cysteine-rich domain / TcdA/TcdB toxin, N-terminal helical domain / TcdB toxin N-terminal helical domain / TcdA/TcdB toxin, catalytic glycosyltransferase domain / TcdA/TcdB catalytic glycosyltransferase domain / SRCR domain / SRCR domain profile. / SRCR-like domain / TcdA/TcdB toxin, pore forming domain / SRCR-like domain superfamily ...Scavenger receptor cysteine-rich domain / TcdA/TcdB toxin, N-terminal helical domain / TcdB toxin N-terminal helical domain / TcdA/TcdB toxin, catalytic glycosyltransferase domain / TcdA/TcdB catalytic glycosyltransferase domain / SRCR domain / SRCR domain profile. / SRCR-like domain / TcdA/TcdB toxin, pore forming domain / SRCR-like domain superfamily / TcdA/TcdB pore forming domain / Scavenger receptor Cys-rich / 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 / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein / 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 family, serine active site. / Serine proteases, trypsin domain profile. / 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 / Maltose/maltodextrin-binding periplasmic protein
Similarity search - Component
Biological speciesHomo sapiens (human) / Paeniclostridium sordellii (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 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-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_36303.png

Downloads & links

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Map

FileDownload / File: emd_36303.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.09 Å/pix.
x 256 pix.
= 278.272 Å		1.09 Å/pix.
x 256 pix.
= 278.272 Å		1.09 Å/pix.
x 256 pix.
= 278.272 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.087 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-5.729135 - 7.51492
Average (Standard dev.)-0.00055739126 (±0.10037074)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 278.272 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_36303_half_map_1.map
Projections & Slices
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Density Histograms

Histogram

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Half map: #2

Fileemd_36303_half_map_2.map
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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: Transmembrane protease serine 2
    • Protein or peptide: Maltose/maltodextrin-binding periplasmic protein,Hemorrhagic toxin

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Supramolecule #1: The TcsH-TMPRSS2 complex

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

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Macromolecule #1: Transmembrane protease serine 2

MacromoleculeName: Transmembrane protease serine 2 / type: protein_or_peptide / ID: 1 / 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 #2: Maltose/maltodextrin-binding periplasmic protein,Hemorrhagic toxin

MacromoleculeName: Maltose/maltodextrin-binding periplasmic protein,Hemorrhagic toxin
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Paeniclostridium sordellii (bacteria)
Molecular weightTheoretical: 87.735609 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MASMTGGQQM GRGSHHHHHH HHMKIEEGKL VIWINGDKGY NGLAEVGKKF EKDTGIKVTV EHPDKLEEKF PQVAATGDGP DIIFWAHDR FGGYAQSGLL AEITPDKAFQ DKLYPFTWDA VRYNGKLIAY PIAVEALSLI YNKDLLPNPP KTWEEIPALD K ELKAKGKS ...String:
MASMTGGQQM GRGSHHHHHH HHMKIEEGKL VIWINGDKGY NGLAEVGKKF EKDTGIKVTV EHPDKLEEKF PQVAATGDGP DIIFWAHDR FGGYAQSGLL AEITPDKAFQ DKLYPFTWDA VRYNGKLIAY PIAVEALSLI YNKDLLPNPP KTWEEIPALD K ELKAKGKS ALMFNLQEPY FTWPLIAADG GYAFKYENGK YDIKDVGVDN AGAKAGLTFL VDLIKNKHMN ADTDYSIAEA AF NKGETAM TINGPWAWSN IDTSKVNYGV TVLPTFKGQP SKPFVGVLSA GINAASPNKE LAKEFLENYL LTDEGLEAVN KDK PLGAVA LKSYEEELAK DPRIAATMEN AQKGEIMPNI PQMSAFWYAV RTAVINAASG RQTVDEALKD AQTGSSSLEV LFQG PEFCT INNEKYYFSY DGILQNGYIT IGRLNFYFDS NNDSKMTTGV FKGPNGFEYF APANTYNNNL EGQAIVYQNK FLTIN GKKY YFDNKSKAVT GWQTIDGKKY YFNPNTAIAA MGWQAIDGKK YYFNPNTAIA TTGWQTIDGK KYYFNPNTAI AATGWQ AID GKKYYFNPNT ATTSIGYTTI NSKNFYFNND GIMQLGVFKG PDGFEYFAPA NTHNNNEEGQ SITYQNKFLI FNEDVYY FD SSSKAVTGWR TIDDHRFYFE PNTGIGANGY KTLDGKNFYF RNGLPQFGVF KGPDGFEYFA PANTHNNNEE GQSITYQN K FLVFLGNRYY FDSSSKAVTG WQTINGNTYY FMPDTAIAAA GGFFTIDGAI YFFGIDGVKQ PGIYG

UniProtKB: Maltose/maltodextrin-binding periplasmic protein, Hemorrhagic toxin

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

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

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 760140
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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