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- PDB-8cmu: High resolution structure of the coagulation Factor XIII A2B2 het... -

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Basic information

Entry
Database: PDB / ID: 8cmu
TitleHigh resolution structure of the coagulation Factor XIII A2B2 heterotetramer complex.
Components
  • Coagulation factor XIII A chain
  • Coagulation factor XIII B chain
KeywordsBLOOD CLOTTING / Factor XIII
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.41 Å
AuthorsSingh, S. / Urgular, D. / Hagelueken, G. / Geyer, M. / Biswas, A.
Funding support Germany, 2items
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, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 11, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Data collection / Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update
Revision 1.2Nov 20, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Coagulation factor XIII A chain
B: Coagulation factor XIII A chain
C: Coagulation factor XIII B chain
D: Coagulation factor XIII B chain


Theoretical massNumber of molelcules
Total (without water)317,9314
Polymers317,9314
Non-polymers00
Water13,475748
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Coagulation factor XIII A chain / Coagulation factor XIIIa / Protein-glutamine gamma-glutamyltransferase A chain / Transglutaminase A chain


Mass: 83365.109 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)
References: UniProt: P00488, protein-glutamine gamma-glutamyltransferase
#2: Protein Coagulation factor XIII B chain / Fibrin-stabilizing factor B subunit / Protein-glutamine gamma-glutamyltransferase B chain / ...Fibrin-stabilizing factor B subunit / Protein-glutamine gamma-glutamyltransferase B chain / Transglutaminase B chain


Mass: 75600.594 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P05160
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 748 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: Factor XIII A2B2 heterotetramer / Type: COMPLEX / Entity ID: #1-#2 / Source: NATURAL
Source (natural)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 / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

Software
NameVersionClassificationNB
phenix.real_space_refine1.20.1_4487refinement
PHENIX1.20.1_4487refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.41 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 333272 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 51 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.002813908
ELECTRON MICROSCOPYf_angle_d0.71218854
ELECTRON MICROSCOPYf_chiral_restr0.04962022
ELECTRON MICROSCOPYf_plane_restr0.01552452
ELECTRON MICROSCOPYf_dihedral_angle_d7.7181864

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