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Biomolecules
Volume 9
Issue 12
10.3390/biom9120765
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Article

The Plasma Factor XIII Heterotetrameric Complex Structure: Unexpected Unequal Pairing within a Symmetric Complex

by
Sneha Singh
1,
Alexis Nazabal
2,
Senthilvelrajan Kaniyappan
3,
Jean-Luc Pellequer
4,
Alisa S. Wolberg
5,
Diana Imhof
6,
Johannes Oldenburg
1 and
Arijit Biswas
1,*
1
Institute of Experimental Hematology and Transfusion medicine, University Hospital of Bonn, Sigmund-Freud Street 25, 53127 Bonn, Germany
2
CovalX, Schützengasse 2, CH-8001 Zürich, Switzerland
3
German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Str. 27, 53127 Bonn, Germany
4
Univ. Grenoble Alpes, CEA, CNRS, IBS, F-38000 Grenoble, France
5
Department of Pathology and Laboratory Medicine and UNC Blood Research Center, University of North Carolina at Chapel Hill, 8018A Mary Ellen Jones Building, Chapel Hill, NC 27599-7035, USA
6
Pharmaceutical Biochemistry and Bioanalytics, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany
*
Author to whom correspondence should be addressed.
Biomolecules 2019, 9(12), 765; https://doi.org/10.3390/biom9120765
Received: 25 October 2019 / Revised: 15 November 2019 / Accepted: 19 November 2019 / Published: 21 November 2019
(This article belongs to the Section Molecular Structure and Dynamics)
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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. View Full-Text
Keywords: coagulation factor XIII complex; threaded modeling; cross-linking mass spectrometry; HADDOCK flexible docking; molecular dynamics simulation; atomic force microscopy; isothermal titration calorimetry coagulation factor XIII complex; threaded modeling; cross-linking mass spectrometry; HADDOCK flexible docking; molecular dynamics simulation; atomic force microscopy; isothermal titration calorimetry
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

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MDPI and ACS Style

Singh, S.; Nazabal, A.; Kaniyappan, S.; Pellequer, J.-L.; Wolberg, A.S.; Imhof, D.; Oldenburg, J.; Biswas, A. The Plasma Factor XIII Heterotetrameric Complex Structure: Unexpected Unequal Pairing within a Symmetric Complex. Biomolecules 2019, 9, 765. https://doi.org/10.3390/biom9120765

AMA Style

Singh S, Nazabal A, Kaniyappan S, Pellequer J-L, Wolberg AS, Imhof D, Oldenburg J, Biswas A. The Plasma Factor XIII Heterotetrameric Complex Structure: Unexpected Unequal Pairing within a Symmetric Complex. Biomolecules. 2019; 9(12):765. https://doi.org/10.3390/biom9120765

Chicago/Turabian Style

Singh, Sneha, Alexis Nazabal, Senthilvelrajan Kaniyappan, Jean-Luc Pellequer, Alisa S. Wolberg, Diana Imhof, Johannes Oldenburg, and Arijit Biswas. 2019. "The Plasma Factor XIII Heterotetrameric Complex Structure: Unexpected Unequal Pairing within a Symmetric Complex" Biomolecules 9, no. 12: 765. https://doi.org/10.3390/biom9120765

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