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- EMDB-16746: High resolution structure of the coagulation Factor XIII A2B2 het... -

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Basic information

Entry
Database: EMDB / ID: EMD-16746
TitleHigh resolution structure of the coagulation Factor XIII A2B2 heterotetramer complex.
Map dataHigh-resolution reconstruction of Factor XIII A2B2 with C2 symmetry.
Sample
  • Complex: Factor XIII A2B2 heterotetramer
    • Protein or peptide: Coagulation factor XIII A chain
    • Protein or peptide: Coagulation factor XIII B chain
  • Ligand: water
KeywordsFactor XIII / BLOOD CLOTTING
Function / homology
Function and homology information


protein-glutamine gamma-glutamyltransferase / protein-glutamine gamma-glutamyltransferase activity / transferase complex / peptide cross-linking / blood coagulation, fibrin clot formation / Common Pathway of Fibrin Clot Formation / platelet alpha granule lumen / blood coagulation / Platelet degranulation / Interleukin-4 and Interleukin-13 signaling ...protein-glutamine gamma-glutamyltransferase / protein-glutamine gamma-glutamyltransferase activity / transferase complex / peptide cross-linking / blood coagulation, fibrin clot formation / Common Pathway of Fibrin Clot Formation / platelet alpha granule lumen / blood coagulation / Platelet degranulation / Interleukin-4 and Interleukin-13 signaling / collagen-containing extracellular matrix / blood microparticle / extracellular space / extracellular region / metal ion binding
Similarity search - Function
: / Transglutaminase, N-terminal / Transglutaminase, C-terminal / Transglutaminase, active site / Protein-glutamine gamma-glutamyltransferase, animal / Transglutaminase, C-terminal domain superfamily / : / Transglutaminase family / Transglutaminase family, C-terminal ig like domain / Transglutaminases active site. ...: / Transglutaminase, N-terminal / Transglutaminase, C-terminal / Transglutaminase, active site / Protein-glutamine gamma-glutamyltransferase, animal / Transglutaminase, C-terminal domain superfamily / : / Transglutaminase family / Transglutaminase family, C-terminal ig like domain / Transglutaminases active site. / Transglutaminase-like superfamily / Transglutaminase/protease-like homologues / Transglutaminase-like / Transglutaminase-like superfamily / Sushi repeat (SCR repeat) / Domain abundant in complement control proteins; SUSHI repeat; short complement-like repeat (SCR) / Sushi/SCR/CCP domain / Sushi/CCP/SCR domain profile. / Sushi/SCR/CCP superfamily / Papain-like cysteine peptidase superfamily / Immunoglobulin E-set / Immunoglobulin-like fold
Similarity search - Domain/homology
Coagulation factor XIII A chain / Coagulation factor XIII B chain
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.41 Å
AuthorsSingh S / Urgular D / Hagelueken G / Geyer M / Biswas A
Funding support Germany, 2 items
OrganizationGrant numberCountry
German Research Foundation (DFG)BI 1645/3-1 Germany
German Research Foundation (DFG)SI 2767-1/1 Germany
CitationJournal: Blood / Year: 2024
Title: Cryo-EM structure of the human native plasma coagulation factor XIII complex.
Authors: Sneha Singh / Gregor Hagelueken / Deniz Ugurlar / Samhitha Urs Ramaraje Urs / Amit Sharma / Manoranjan Mahapatra / Friedel Drepper / Diana Imhof / Pitter F Huesgen / Johannes Oldenburg / ...Authors: Sneha Singh / Gregor Hagelueken / Deniz Ugurlar / Samhitha Urs Ramaraje Urs / Amit Sharma / Manoranjan Mahapatra / Friedel Drepper / Diana Imhof / Pitter F Huesgen / Johannes Oldenburg / Matthias Geyer / Arijit Biswas /
Abstract: The structure of human coagulation factor XIII (FXIII), a heterotetrameric plasma pro-transglutaminase that covalently crosslinks pre-formed fibrin polymers, remains elusive until today. The ...The structure of human coagulation factor XIII (FXIII), a heterotetrameric plasma pro-transglutaminase that covalently crosslinks pre-formed fibrin polymers, remains elusive until today. The heterotetrameric complex is composed of two catalytic FXIII-A and two protective FXIII-B subunits. Structural etiology underlying FXIII deficiency has so far been derived from crystallographic structures, all of which are currently available for the FXIII-A2 homodimer only. Here, we present the cryo-electron microscopy structure of a native, human plasma-derived FXIII-A2B2 complex at 2.4 Å resolution. The structure provides detailed information on FXIII subunit interacting interfaces as the two subunits interact strongly in plasma. The native FXIII-A2B2 complex reveals a pseudo-symmetric heterotetramer of two FXIII-B monomers intercalating with a symmetric FXIII-A2 dimer forming a "crown-like" assembly. The symmetry axes of the A2 and B2 homodimers are twisted relative to each other such that Sushi domain 1 interacts with the catalytic core of the A subunit and Sushi domain 2 with the symmetry related A' subunit and vice versa. We also report four novel mutations in the F13A1 gene encoding the FXIII-A subunit from a cohort of patients with severe FXIII deficiency. Our structure reveals the etiological basis of homozygous and heterozygous pathogenic mutations and explains the conditional dominant negative effects of heterozygous mutations. This atomistic description of complex interfaces is consistent with previous biochemical data and shows a congruence between the structural biochemistry of the FXIII complex and the clinical features of FXIII deficiency.
History
DepositionFeb 21, 2023-
Header (metadata) releaseSep 11, 2024-
Map releaseSep 11, 2024-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_16746.png

Downloads & links

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Map

FileDownload / File: emd_16746.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHigh-resolution reconstruction of Factor XIII A2B2 with C2 symmetry.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.7 Å/pix.
x 512 pix.
= 356.864 Å		0.7 Å/pix.
x 512 pix.
= 356.864 Å		0.7 Å/pix.
x 512 pix.
= 356.864 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.697 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0899
Minimum - Maximum-0.80668765 - 1.165683
Average (Standard dev.)0.000084790416 (±0.019512907)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 356.864 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map A

Fileemd_16746_half_map_1.map
AnnotationHalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_16746_half_map_2.map
AnnotationHalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Factor XIII A2B2 heterotetramer

EntireName: Factor XIII A2B2 heterotetramer
Components
  • Complex: Factor XIII A2B2 heterotetramer
    • Protein or peptide: Coagulation factor XIII A chain
    • Protein or peptide: Coagulation factor XIII B chain
  • Ligand: water

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Supramolecule #1: Factor XIII A2B2 heterotetramer

SupramoleculeName: Factor XIII A2B2 heterotetramer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Coagulation factor XIII A chain

MacromoleculeName: Coagulation factor XIII A chain / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: protein-glutamine gamma-glutamyltransferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 83.365109 KDa
SequenceString: MSETSRTAFG GRRAVPPNNS NAAEDDLPTV ELQGVVPRGV NLQEFLNVTS VHLFKERWDT NKVDHHTDKY ENNKLIVRRG QSFYVQIDF SRPYDPRRDL FRVEYVIGRY PQENKGTYIP VPIVSELQSG KWGAKIVMRE DRSVRLSIQS SPKCIVGKFR M YVAVWTPY ...String:
MSETSRTAFG GRRAVPPNNS NAAEDDLPTV ELQGVVPRGV NLQEFLNVTS VHLFKERWDT NKVDHHTDKY ENNKLIVRRG QSFYVQIDF SRPYDPRRDL FRVEYVIGRY PQENKGTYIP VPIVSELQSG KWGAKIVMRE DRSVRLSIQS SPKCIVGKFR M YVAVWTPY GVLRTSRNPE TDTYILFNPW CEDDAVYLDN EKEREEYVLN DIGVIFYGEV NDIKTRSWSY GQFEDGILDT CL YVMDRAQ MDLSGRGNPI KVSRVGSAMV NAKDDEGVLV GSWDNIYAYG VPPSAWTGSV DILLEYRSSE NPVRYGQCWV FAG VFNTFL RCLGIPARIV TNYFSAHDND ANLQMDIFLE EDGNVNSKLT KDSVWNYHCW NEAWMTRPDL PVGFGGWQAV DSTP QENSD GMYRCGPASV QAIKHGHVCF QFDAPFVFAE VNSDLIYITA KKDGTHVVEN VDATHIGKLI VTKQIGGDGM MDITD TYKF QEGQEEERLA LETALMYGAK KPLNTEGVMK SRSNVDMDFE VENAVLGKDF KLSITFRNNS HNRYTITAYL SANITF YTG VPKAEFKKET FDVTLEPLSF KKEAVLIQAG EYMGQLLEQA SLHFFVTARI NETRDVLAKQ KSTVLTIPEI IIKVRGT QV VGSDMTVTVE FTNPLKETLR NVWVHLDGPG VTRPMKKMFR EIRPNSTVQW EEVCRPWVSG HRKLIASMSS DSLRHVYG E LDVQIQRRPS M

UniProtKB: Coagulation factor XIII A chain

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Macromolecule #2: Coagulation factor XIII B chain

MacromoleculeName: Coagulation factor XIII B chain / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 75.600594 KDa
SequenceString: MRLKNLTFII ILIISGELYA EEKPCGFPHV ENGRIAQYYY TFKSFYFPMS IDKKLSFFCL AGYTTESGRQ EEQTTCTTEG WSPEPRCFK KCTKPDLSNG YISDVKLLYK IQENMRYGCA SGYKTTGGKD EEVVQCLSDG WSSQPTCRKE HETCLAPELY N GNYSTTQK ...String:
MRLKNLTFII ILIISGELYA EEKPCGFPHV ENGRIAQYYY TFKSFYFPMS IDKKLSFFCL AGYTTESGRQ EEQTTCTTEG WSPEPRCFK KCTKPDLSNG YISDVKLLYK IQENMRYGCA SGYKTTGGKD EEVVQCLSDG WSSQPTCRKE HETCLAPELY N GNYSTTQK TFKVKDKVQY ECATGYYTAG GKKTEEVECL TYGWSLTPKC TKLKCSSLRL IENGYFHPVK QTYEEGDVVQ FF CHENYYL SGSDLIQCYN FGWYPESPVC EGRRNRCPPP PLPINSKIQT HSTTYRHGEI VHIECELNFE IHGSAEIRCE DGK WTEPPK CIEGQEKVAC EEPPFIENGA ANLHSKIYYN GDKVTYACKS GYLLHGSNEI TCNRGKWTLP PECVENNENC KHPP VVMNG AVADGILASY ATGSSVEYRC NEYYLLRGSK ISRCEQGKWS SPPVCLEPCT VNVDYMNRNN IEMKWKYEGK VLHGD LIDF VCKQGYDLSP LTPLSELSVQ CNRGEVKYPL CTRKESKGMC TSPPLIKHGV IISSTVDTYE NGSSVEYRCF DHHFLE GSR EAYCLDGMWT TPPLCLEPCT LSFTEMEKNN LLLKWDFDNR PHILHGEYIE FICRGDTYPA ELYITGSILR MQCDRGQ LK YPRCIPRQST LSYQEPLRT

UniProtKB: Coagulation factor XIII B chain

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Macromolecule #3: water

MacromoleculeName: water / type: ligand / ID: 3 / Number of copies: 748 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k 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: 1.8 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: Alphafold2 model
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.41 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 333272
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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