Arijit Biswas Lab
The Biochemical-IT laboratory, at the Institute of Experimental Hematology and Transfusion Medicine, University Hospital of Bonn.
What do we do?
Despite remarkable advances made in the technology of structure determination of complexes especially in the context of cryo-EM, there are many protein complexes that owing to their unique biochemical and biophysical properties escape structural determination by traditional techniques. With decades-long history of knowing about the coagulation cascade, and the responsible proteins involved, we still lack at having structure-function data for the coagulation proteins. Several proteins belonging to the coagulation cascade escape the traditional methods for structural characterization owing to the complex structures, which are also transient in nature, this explains the present insufficiency in structural data. In our lab, we aim to characterize such biomolecules from its genetic level to its structure-functional aspects by employing a multitude of techniques. We aim to start from protein to complexes, to networks and proteome, that will assess the importance of detected interactions on a system-wide level, here coagulation. We have an extensive experience in clinical, genetic, and epidemiological studies of coagulation factors, specifically Factor XIII, which aides us in further structure-function characterization as well.
The focus of our group is on characterizing the genetic- structural-functional aspects of coagulation proteins using an array of biochemical and computational approaches. Our main protein of interest is the Coagulation Factor XIII (FXIII), which is a plasma circulating pro-transglutaminase complex responsible for covalent crosslinking of the pre-formed soluble fibrin clot converting it to a insoluble one resistant to premature fibrinolysis. Inherited deficiency of Factor XIII (FXIII) is a rare coagulation disorder which results in severe bleeding diathesis. The severe form of FXIII deficiency is caused by homozygous or compound heterozygous mutations in FXIII genes. Investigations from our group have suggested the existence of a mild form of FXIII deficiency as well resulting exclusively from heterozygous genetic variants. Furthermore, using a clustered approach involving in-silico modelling complemented by biochemical analyses, our group has shed light on the activation mode of FXIII, roles of Calcium binding to FXIII, regulatory importance of the FXIIIB subunit and its genetic variability amongst other things. Our group recently used an integrative hybrid approach to build the first full-atom structural model for the plasma FXIII complex.
What do you mean by Factor XIII?
• FXIII is a human plasma transglutaminase that acts at the terminal stage of blot clot formation, by stabilizing the pre-formed clot.
• It exists in plasma as a heterotetrameric complex, with dimeric-catalytic FXIII-A subunits complexed non covalently with dimeric-regulatory FXIII-B subunits. During vascular injury, thrombin mediated cleavage of FXIII-A subunits, along with Calcium binding activates the zymogen to its active form.
• Deficiency of FXIII causes mild to severe bleeding predispositions, ranging from undetectable nose bleeds to fatal intracranial haemorrhages.
• FXIII is also associated with thrombosis although its exact role in thrombotic pathophysiology is currently under investigation.
• Recent presentation of all-atom structural model of plasma Factor XIII heterotetrameric complex has been elucidated by an integrative hybrid approach employing analytical biochemistry, structural biochemistry, and computational modelling. The approach has revealed significant patches present on participating subunits that act as structural interfaces for complex formation and its activation-based dissociation in plasma.
• Recent advances in thrombosis research are paving its way towards development of FXIII specific inhibitors as futuristic tools for clot thinning.
Our former and present Collaborators and supporters
Our research activities are supported by funding received from DFG, international research bodies like WFH and from industry based competitive grants provided to PD Dr. Arijit Biswas and Prof. Oldenburg (Shire, CSL-Behring, Novo Nordisk, Bayer and Biotest to name a few).Apart from FXIII, we collaborate with multiple other groups in structure functional investigations of other coagulation proteins like vWF, Factor VIII and VKORC1. We also are involved in generating inhibitors that will work in pro-coagulant scenarios in close collaboration with Prof. Diana Imhof from Pharmaceutical Institute in University of Bonn.