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Factor XIII topology: organization of B subunits and changes with activation studied with single‐molecule atomic force microscopy
Author(s): ,
Anna D. Protopopova
Affiliations:
Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, USA
,
Andrea Ramirez
Affiliations:
Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, USA. Border Biomedical Research Center, Department of Biological Sciences, University of Texas at El Paso, El Paso, USA
,
Dmitry V. Klinov
Affiliations:
Federal Research and Clinical Center of Physical‐Chemical Medicine, Moscow, Russian Federation
,
Rustem I. Litvinov
Affiliations:
Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, USA. Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russian Federation
John W. Weisel
Affiliations:
Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, USA
Correspondence: John W. Weisel, room 1154, BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104‐6058, USA|Tel.: +1 215 898 3573|E‐mail: weisel@pennmedicine.upenn.edu
ISTH Academy. W. Weisel J.
May 1, 2019; 273609
John W. Weisel
John  W. Weisel
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Journal Abstract
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Background
Factor XIII (FXIII) is a precursor of the blood plasma transglutaminase (FXIIIa) that is generated by thrombin and Ca and covalently crosslinks fibrin to strengthen blood clots. Inactive plasma FXIII is a heterotetramer with two catalytic A subunits and two non‐catalytic B subunits. Inactive A subunits have been characterized crystallographically, whereas the atomic structure of the entire FXIII and B subunits is unknown and the oligomerization state of activated A subunits remains controversial.
Objectives
Our goal was to characterize the (sub)molecular structure of inactive FXIII and changes upon activation.
Methods
Plasma FXIII, non‐activated or activated with thrombin and Ca, was studied by single‐molecule atomic force microscopy. Additionally, recombinant separate A and B subunits were visualized and compared with their conformations and dimensions in FXIII and FXIIIa.
Results and Conclusions
We showed that heterotetrameric FXIII forms a globule composed of two catalytic A subunits with two flexible strands comprising individual non‐catalytic B subunits that protrude on one side of the globule. Each strand corresponds to seven to eight out of 10 tandem repeats building each B subunit, called sushi domains. The remainder were not seen, presumably because they were tightly bound to the globular A dimer. Some FXIII molecules had one or no visible strands, suggesting dissociation of the B subunits from the globular core. After activation of FXIII with thrombin and Ca, B subunits dissociated and formed B homodimers, whereas the activated globular A subunits dissociated into monomers. These results characterize the molecular organization of FXIII and changes with activation.
Keyword(s)
atomic force microscopy, blood, blood coagulation factor, factor XIII, transglutaminases
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