TY  - JOUR
AU  - Singh, Sneha
AU  - Nazabal, Alexis
AU  - Kaniyappan, Senthilvelrajan
AU  - Pellequer, Jean-Luc
AU  - Wolberg, Alisa S
AU  - Imhof, Diana
AU  - Oldenburg, Johannes
AU  - Biswas, Arijit
TI  - The Plasma Factor XIII Heterotetrameric Complex Structure: Unexpected Unequal Pairing within a Symmetric Complex.
JO  - Biomolecules
VL  - 9
IS  - 12
SN  - 2218-273X
CY  - Basel
PB  - MDPI
M1  - DZNE-2020-00384
SP  - 765
PY  - 2019
AB  - 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.
KW  - Calcium: pharmacology
KW  - Factor XIII: chemistry
KW  - HEK293 Cells
KW  - Humans
KW  - Molecular Docking Simulation
KW  - Protein Conformation
KW  - Protein Multimerization
KW  - Protein Subunits: chemistry
KW  - Thermodynamics
KW  - Thrombin: pharmacology
LB  - PUB:(DE-HGF)16
C6  - pmid:31766577
C2  - pmc:PMC6995596
DO  - DOI:10.3390/biom9120765
UR  - https://pub.dzne.de/record/145024
ER  -