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Structural biochemistry and bioinformatics-AG PD Dr. Arijit Biswas

Focus of research:

Our vision is to develop advanced therapeutics for individuals with thrombotic and bleeding complications, including unexplained bleeding, rare bleeding disorders, and acquired bleeding/thrombosis conditions. To achieve this long-term goal, our mission is to explore the genetic, functional, and structural aspects of the unique coagulation cascade.

Our research activities are supported by funding from both governmental and industry-based initiatives. Our findings are regularly published in leading journals, which can be accessed via the following link:

 https://www.ncbi.nlm.nih.gov/myncbi/1XMrxSbZr4vAi/bibliography/public/

Lab website: www.arijitbiswaslab.com

Over the past decade, our research has brought us closer to realizing the potential of Coagulation Factor XIII (FXIII) as a therapeutic agent for mild bleeding disorders and as a drug candidate for thrombotic scenarios. One of our key objectives is to understand the functional impact of structural-genetic variants in coagulation factor genes, with the ultimate goal of developing improved therapies for clinical use.

FXIII is a plasma-circulating pro-transglutaminase complex that plays a crucial role in covalently crosslinking pre-formed soluble fibrin clots, making them mechanically stronger and resistant to fibrinolysis. Inherited FXIII deficiency is a rare coagulation disorder caused by homozygous or compound heterozygous mutations in the FXIII genes (F13A1, F13B), leading to severe bleeding diathesis. Our research has also identified a mild form of FXIII deficiency resulting from heterozygous genetic variants. This discovery has been further explored by Dr. Anne Thomas, a former PhD student, who demonstrated the causality of these variants by expressing them in a heterologous system. Building on this work, an ongoing PhD project led by Mr. Haroon Javed focuses on isolating these heterozygotes in their pure state.

Using a combined approach of in silico modeling and biochemical analyses, our team has provided insights into the activation mode, behavior, and regulation of the FXIII complex (FXIII-A2B2), as well as its constituent proteins (FXIII-A and FXIII-B). This research, led by Dr. Sneha Singh, has been instrumental in developing the first all-atomic structural model of this plasma complex. Our expertise in hybrid methodologies for structural characterization has been a key strength of our group. Working with coagulation proteins presents significant challenges due to the transient nature of many complexes, their existence as large supra-molecular structures, or their problematic maturation in plasma. To overcome these challenges, we collaborate closely with structural biology groups across Europe, utilizing state-of-the-art biophysical and bioanalytical facilities. Recently, Dr. Sneha Singh successfully resolved a 2.4Å cryo-EM structure of the FXIII complex, in collaboration with the Thermo-Fischer cryo-EM facility in the Netherlands and the Institute of Structural Biology in Bonn.

Building on a similar approach, PhD student Ms. Samhitha Urs is working on gaining structural insights into the full-length structure of Factor VIII (FVIII-FL, with B domain), which currently lacks high-resolution structural data. FVIII is associated with Hemophilia A, a common inherited bleeding disorder, and is treated with various therapies, including frequent administration of plasma-derived FVIII, recombinant FVIII, and gene therapy. We are employing hybrid methodologies ranging from low-to-high resolution microscopy, such as AFM and cryo-EM, to resolve the structure of FVIII-FL's heavily glycosylated B domain.

Another PhD student, Md. Mubassherul Islam, is using computational approaches to develop small molecule inhibitors targeting FXIII for pro-coagulant scenarios. This work is being conducted in close collaboration with Prof. Diana Imhof at the Pharmaceutical Institute, University of Bonn. Additionally, Mubassherul is using machine learning techniques to create pipelines for structure-functional predictions, particularly in understanding the pathomolecular mechanisms underlying missense mutations.

Beyond FXIII and FVIII, our group collaborates with multiple research teams to explore the structure-functional relationships of other coagulation factors such as vWF, Factor V, VKORC1, and Fibrinogen. These collaborations are part of our broader effort to advance structure-based coagulation research.

Dr. Sneha Singh, a key member of our group with several grants and awards to her credit, is currently investigating the structural role of the FXIII-Fibrinogen complex in clot architecture. She is also leading a detailed study of the proteomic signatures underlying various forms of thrombosis, particularly within the fibrinolytic pathway (FXIII-Fibrinogen axis).

  • Investigating the structural role of the FXIII-Fibrinogen complex in clot architecture.
  • Analyzing proteomic signatures underlying various forms of thrombosis, particularly within the fibrinolytic pathway (FXIII-Fibrinogen axis).
  • Exploring the pharmacological potential of FXIII as a drug target.
  • Identifying the significance of the B domain in full-length coagulation Factor VIII.
  • Using machine learning to enhance diagnostic predictability of rare coagulation disorders and to improve structure-functional predictions for missense mutations.
  • Prof. Matthias Geyer, Director, Institute of Structural Biology, Biomedical Center, University of Bonn
  • PD Dr. Gregor Hagelüken, Institute of Structural Biology, Biomedical Center, University of Bonn
  • Prof. Diana Imhof, Pharmaceutical Institute, University of Bonn
  • Prof. Manoranjan Mahapatra, Department of Hematology All India Institute of Medical Sciences, New Delhi, India.
  • Prof. Alisa Wolberg, Department of Pathology and Laboratory Medicine, Chapel Hill, United States

Singh S, Hagelueken G, Ugurlar D, Ramaraje Urs SU, Sharma A, Mahapatra M, Imhof D, Oldenburg J, Geyer M, Biswas A. A 2.4 Å Cryo-EM structure of the Human Native Plasma Coagulation Factor XIII-A2B2 Complex. (under revision in Blood).

Singh S, Pezeshkpoor B, Jamil MA, Dodt J, Sharma A, Ramar V, Ivaskevicius V, Hethershaw E, Philippou H, Pavlova A, Oldenburg J, Biswas A. Heterozygosity in factor XIII genes and the manifestation of mild inherited factor XIII deficiency. J Thromb Haemost. 2024 Feb;22(2):379-393.

Hopp MT, Ugurlar D, Pezeshkpoor B, Biswas A, Ramoji A, Neugebauer U, Oldenburg J, Imhof D. In-depth structure-function profiling of the complex formation between clotting factor VIII and heme. Thromb Res. 2024 May;237:184-195. 

Haas B, Hass MDS, Voltz A, Vogel M, Walther J, Biswas A, Hass D, Pfeifer A. Sulfonylureas exert antidiabetic action on adipocytes by inhibition of PPARγ serine 273 phosphorylation. Mol Metab. 2024 Jul;85:101956. 

Desage S, Leuci A, Enjolras N, Holle LA, Singh S, Delavenne X, Wolberg AS, Biswas A, Dargaud Y. Characterization of a recombinant factor IX molecule fused to coagulation factor XIII-B subunit. Haemophilia. 2023 Nov;29(6):1483-1489.

Javed H, Singh S, Ramaraje Urs SU, Oldenburg J, Biswas A. Genetic landscape in coagulation factor XIII associated defects - Advances in coagulation and beyond. Blood Rev. 2023 May;59:101032. 

Akhter MS, Hamali HA, Mobarki AA, Rashid H, Oldenburg J, Biswas A. SARS-CoV-2 Infection: Modulator of Pulmonary Embolism Paradigm. J Clin Med. 2021 Mar 4;10(5):1064.

Akhter MS, Hamali HA, Rashid H, Dobie G, Madkhali AM, Mobarki AA, Oldenburg J, Biswas A. Mitochondria: Emerging Consequential in Sickle Cell Disease. J Clin Med. 2023 Jan 18;12(3):765.

Ivaškevičius V, Biswas A, Singh S, Stulpinaitė U, Reda S, Rühl H, Pezeshkpoor B, Pavlova A, Oldenburg J. Fibrinogen Bonn (p. Arg510Cys) in the Aα-Chain Is Associated with High Risk of Venous Thrombosis. Hamostaseologie. 2023 Dec;43(6):440-446. 

Jamil MA, Singh S, El-Maarri O, Oldenburg J, Biswas A. Exploring Diverse Coagulation Factor XIII Subunit Expression Datasets: A Bioinformatic Analysis. Int J Mol Sci. 2022 Apr 25;23(9):4725. 

Ghosh S, Kraus K, Biswas A, Müller J, Forin F, Singer H, Höning K, Hornung V, Watzka M, Oldenburg J, Czogalla-Nitsche KJ. GGCX variants leading to biallelic deficiency to γ-carboxylate GRP cause skin laxity in VKCFD1 patients. Hum Mutat. 2022 Jan;43(1):42-55. 

Hopp MT, Alhanafi N, Paul George AA, Hamedani NS, Biswas A, Oldenburg J, Pötzsch B, Imhof D. Molecular Insights and Functional Consequences of the Interaction of Heme with Activated Protein C. Antioxid Redox Signal. 2021 Jan 1;34(1):32-48. 

Schmitz T, Paul George AA, Nubbemeyer B, Bäuml CA, Steinmetzer T, Ohlenschläger O, Biswas A, Imhof D. NMR-Based Structural Characterization of a Two-Disulfide-Bonded Analogue of the FXIIIa Inhibitor Tridegin: New Insights into Structure-Activity Relationships. Int J Mol Sci. 2021 Jan 17;22(2):880. 

Rad F, Dabbagh A, Dorgalaleh A, Biswas A. The Relationship between Inflammatory Cytokines and Coagulopathy in Patients with COVID-19. J Clin Med. 2021 May 9;10(9):2020.

Ramezanpour N, Zaker F, Biswas A, Dorgalaleh A. Inhibitor in Congenital Factor VII Deficiency; a Rare but Serious Therapeutic Challenge-A Systematic Literature Review. J Clin Med. 2021 Jan 8;10(2):211. 

Yadegari H, Biswas A, Ahmed S, Naz A, Oldenburg J. von Willebrand factor propeptide missense variants affect anterograde transport to Golgi resulting in ER retention. Hum Mutat. 2021 Jun;42(6):731-744. 

Hamedani NS, Biswas A, Rudan O, Tönges R, Meyring C, Tolle F, Mayer G, Oldenburg J, Müller J, Pötzsch B. Functional and Structural Characterization of Nucleic Acid Ligands That Bind to Activated Coagulation Factor XIII. J Clin Med. 2021 Feb 10;10(4):677. 

Sharma A, Tobar-Tosse F, Chand Dakal T, Liu H, Biswas A, Menon A, Paruchuri A, Katsonis P, Lichtarge O, Gromiha MM, Ludwig M, Schmidt-Wolf IGH, Holz FG, Loeffler KU, Herwig-Carl MC. PPAR-Responsive Elements Enriched with Alu Repeats May Contribute to Distinctive PPARγ-DNMT1 Interactions in the Genome. Cancers (Basel). 2021 Aug 7;13(16):3993.

Bhakuni T, Sharma A, Biswas A, Bano S, Mahapatra M, Saxena R, Jairajpuri MA. Identification and characterization of a novel variant in C-terminal region of Antithrombin (Ala427Thr) associated with type II AT deficiency leading to polymer formation. J Thromb Thrombolysis. 2020 Oct;50(3):678-685.

Bäuml CA, Paul George AA, Schmitz T, Sommerfeld P, Pietsch M, Podsiadlowski L, Steinmetzer T, Biswas A, Imhof D. Distinct 3-disulfide-bonded isomers of tridegin differentially inhibit coagulation factor XIIIa: The influence of structural stability on bioactivity. Eur J Med Chem. 2020 Sep 1;201:112474. 

Singh S, Nazabal A, Kaniyappan S, Pellequer JL, Wolberg AS, Imhof D, Oldenburg J, Biswas A. The Plasma Factor XIII Heterotetrameric Complex Structure: Unexpected Unequal Pairing within a Symmetric Complex. Biomolecules. 2019 Nov 21;9(12):765. IF: 4.6

Singh S, Dodt J, Volkers P, Hethershaw E, Philippou H, Ivaskevicius V, Imhof D, Oldenburg J, Biswas A. Structure functional insights into calcium binding during the activation of coagulation factor XIII A. Sci Rep. 2019 Aug 5;9(1):11324.

Singh S, Akhter MS, Dodt J, Volkers P, Reuter A, Reinhart C, Krettler C, Oldenburg J, Biswas A. Identification of Potential Novel Interacting Partners for Coagulation Factor XIII B (FXIII-B) Subunit, a Protein Associated with a Rare Bleeding Disorder. Int J Mol Sci. 2019 May 31;20(11).

Singh S, Akhter MS, Dodt J, Sharma A, Kaniyappan S, Yadegari H, Ivaskevicius V, Oldenburg J, Biswas A. Disruption of Structural Disulfides of Coagulation FXIII-B Subunit; Functional Implications for a Rare Bleeding Disorder. Int J Mol  Sci. 2019 Apr 22;20(8). pii: E1956. I

Akhter MS, Singh S, Yadegari H, Ivaskevicius V, Oldenburg J, Biswas A. Exploring the structural similarity yet functional distinction between coagulation factor XIII-B and complement factor H sushi domains. J Thromb Thrombolysis. 2019 Jul;48(1):95-102.

Mubasherul islam:

2022: Recipient of Best Poster award at Hamburg Haemophilia Symposium

 

Ms. Samhitha Urs Ramaraje Urs:

  2023: Recipient of Rudolf-Marx-Stipedium at GTH 2023

  2022: Recipient of Best Poster award at Hamburg Haemophilia Symposium

 

Dr. Sneha Singh

2020: Recognition as Young Talent in the field of Bleeding disorders (Nachwucshsförderpreise Blutungskrankheiten 2020) for contributions towards bleeding disorders, by the German Society for Thrombosis and Hemostasis (Gesellschaft for thrombose heamatosis (GTH))

2021: Recipient of funding by German Research Foundation (DFG), under module SI 2767 1/1: Temporary position for Principal Investigator

(Starting from April 2021)

2021: Recipient of funding (for material costs) by the German Society of Thrombosis and Hemostasis (GTH) under Early Career Research Grants-2021.

2021: Recipient of Bayer Promotionspriese-2021.

2022: Recipient of the Gunter-Landbeck Excellence Award in hemophilia-2022, at the Hamburg Hemophilia Symposium organized by Takeda.

2023: Recipient of funding by German Research Foundation (DFG), under module SI 2767 1/2

2023: Recipient of Prof Heimburger award-2023

2023: Recipient of the Best-Oral abstract award at the annual GTH-2023 meeting, in Frankfurt

2023: EMBO grant to participate in EMBO Practical Course Integrative Modelling of Protein Interactions from 17 – 22 September 2023 in Izmir, Türkiye

2024: Recipient of Post-Doc Innovation funds-2023/2, by the Immunosensation2 Cluster of Excellence, University of Bonn

 

PD Dr. Arijit Biswas:

2019: Recipient of a DFG grant for the project entitled “Functional investigations into the dominant-negative patho-molecular mechanisms underlying FXIII heterozygous missense mutations of emerging clinical importance.” (Grant number BI 1645/3-1).

2019: Recipient of an Investigator initiated research grant from Takeda-Shire for the project entitled “Exploring the conformational landscape of factor VIII B domain in order to generate an all atom full length structure of the coagulation factor VIII protein.” (Grant number: N-045.299).

2019: Recipient of a “Grants4Target” grant from Bayer for the project entitled “Exploring the conformational landscape of factor VIII B domain in order to generate an all atom full length structure of the coagulation factor VIII protein.” (Grant number: N-045.299). (Grant number: H-045.0314).

2019: Recipient of a DFG grant for the project entitled “Functional investigations into the dominant-negative patho-molecular mechanisms underlying FXIII heterozygous missense mutations of emerging clinical importance.” (Grant number BI 1645/3-1).

2019: Recipient of an Investigator initiated research grant from Shire for the project entitled “Exploring the conformational landscape of factor VIII B domain in order to generate an all atom full length structure of the coagulation factor VIII protein.” (Grant number: N-045.299).

2019: Recipient of a “Grants4Target” grant from Bayer for the project entitled  (Grant number: H-045.0314).

2021: Recipient of GLEA 2021 (Günter Landbeck Excellence Award)

2023: Recipient of DHSF grant “Entwicklungsfähigkeit vom Wirkstoff zum Arzneimittel: Fallstudie über Peptid- und niedermolekulare Inhibitoren des Blutgerinnungsfaktors XIIIa”.

We are always looking for talented PhD and Master’s students to join our team. For inquiries about current positions, please contact Enable JavaScript to view protected content. or Enable JavaScript to view protected content.

 
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