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image of The Structural Analogy of MASP-2 with Thrombin and MASP-1 Reveals Strong Binding with PAR4

Abstract

Introduction

The historical discovery that thrombin activates Protease-Activated Receptor 4 (PAR4) has paved the way for several novel findings. Besides thrombin, the complement lectin pathway protease Mannose-Binding Lectin-Associated Serine Protease-1 (MASP-1) also binds to PAR4, albeit with lower affinity. Similar to thrombin, MASP-1 activates Ca2+ signaling pathways in endothelial cells. MASP-2, a homolog of MASP-1, plays an important role in complement activation; however, its direct interaction with PAR4 has not yet been elucidated. In this study, we performed structural investigations of thrombin, MASP-1, and MASP-2 to evaluate their binding affinities toward the PAR4 peptide.

Methods

We employed docking, binding affinity calculations, molecular dynamics simulations, and mutagenesis studies to test our hypothesis.

Results

For the first time, we demonstrate that, like thrombin and MASP-1, MASP-2 binds to PAR4 with appreciable affinity and could serve as a potential agonist of the PAR4 receptor and its associated inflammatory signaling pathways.

Discussion

The high sequence similarity of MASP-2 with MASP-1 and thrombin is an important factor in attaining comparable binding with the PAR4 peptide.

Conclusion

Our findings may pave the way for future investigations into the signaling mechanisms and therapeutic potential of PAR4-mediated inflammatory diseases.

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2026-01-20
2026-01-31

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The Structural Analogy of MASP-2 with Thrombin and MASP-1 Reveals Strong Binding with PAR4
Bentham Science Publishers ; https://doi.org/10.2174/0118715230411505251126063432
/content/journals/aiaamc/10.2174/0118715230411505251126063432
/content/journals/aiaamc/10.2174/0118715230411505251126063432
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  • Article Type:     Research Article
Keywords: complement system ; MASP-2 ; thrombin ; MASP-1 ; PAR4

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