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@ARTICLE{Singh:145024,
      author       = {Singh, Sneha and Nazabal, Alexis and Kaniyappan,
                      Senthilvelrajan and Pellequer, Jean-Luc and Wolberg, Alisa S
                      and Imhof, Diana and Oldenburg, Johannes and Biswas, Arijit},
      title        = {{T}he {P}lasma {F}actor {XIII} {H}eterotetrameric {C}omplex
                      {S}tructure: {U}nexpected {U}nequal {P}airing within a
                      {S}ymmetric {C}omplex.},
      journal      = {Biomolecules},
      volume       = {9},
      number       = {12},
      issn         = {2218-273X},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DZNE-2020-00384},
      pages        = {765},
      year         = {2019},
      abstract     = {Factor XIII (FXIII) is a predominant determinant of clot
                      stability, strength, and composition. Plasma FXIII
                      circulates as a pro-transglutaminase with two catalytic A
                      subunits and two carrier-protective B subunits in a
                      heterotetramer (FXIII-A2B2). FXIII-A2 and -B2 subunits are
                      synthesized separately and then assembled in plasma.
                      Following proteolytic activation by thrombin and
                      calcium-mediated dissociation of the B subunits, activated
                      FXIII (FXIIIa) covalently cross links fibrin, promoting clot
                      stability. The zymogen and active states of the FXIII-A
                      subunits have been structurally characterized; however, the
                      structure of FXIII-B subunits and the FXIII-A2B2 complex
                      have remained elusive. Using integrative hybrid approaches
                      including atomic force microscopy, cross-linking mass
                      spectrometry, and computational approaches, we have
                      constructed the first all-atom model of the FXIII-A2B2
                      complex. We also used molecular dynamics simulations in
                      combination with isothermal titration calorimetry to
                      characterize FXIII-A2B2 assembly, activation, and
                      dissociation. Our data reveal unequal pairing of individual
                      subunit monomers in an otherwise symmetric complex, and
                      suggest this unusual structure is critical for both assembly
                      and activation of this complex. Our findings enhance
                      understanding of mechanisms associating FXIII-A2B2 mutations
                      with disease and have important implications for the
                      rational design of molecules to alter FXIII assembly or
                      activity to reduce bleeding and thrombotic complications.},
      keywords     = {Calcium: pharmacology / Factor XIII: chemistry / HEK293
                      Cells / Humans / Molecular Docking Simulation / Protein
                      Conformation / Protein Multimerization / Protein Subunits:
                      chemistry / Thermodynamics / Thrombin: pharmacology},
      cin          = {AG Mandelkow 2},
      ddc          = {570},
      cid          = {I:(DE-2719)1013015},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31766577},
      pmc          = {pmc:PMC6995596},
      doi          = {10.3390/biom9120765},
      url          = {https://pub.dzne.de/record/145024},
}