Hemostasis relies on a reaction network of serine proteases and their cofactors to form a blood clot. Coagulation factor IXa (protease) plays an essential role in hemostasis as evident from the bleeding disease associated with its absence. RNA aptamers specifically targeting individual coagulation factors have potential as anticoagulants and as probes of the relationship between structure and function. Here, we report X-ray structures of human factor IXa without a ligand bound to the active site either in the apo-form or in complex with an inhibitory aptamer specific for factor IXa. The aptamer binds to an exosite in the catalytic domain and allosterically distorts the active site. Our studies reveal a conformational ensemble of IXa states, wherein large movements of Trp215 near the active site drive functional transitions between the closed (aptamer-bound), latent (apo), and open (substrate-bound) states. The latent state of the apo-enzyme may bear on the uniquely poor catalytic activity of IXa compared to other coagulation proteases. The exosite, to which the aptamer binds, has been implicated in binding VIIIa and heparin, both of which regulate IXa function. Our findings reveal the importance of exosite-driven allosteric modulation of IXa function and new strategies to rebalance hemostasis for therapeutic gain.

Blood coagulation and cancer are intrinsically connected, hypercoagulation-associated thrombotic complications are commonly observed in certain types of cancer, often leading to decreased survival in cancer patients. Apart from the common role in coagulation, coagulation proteases often trigger intracellular signaling in various cancers via the activation of a G protein-coupled receptor superfamily protease: protease-activated receptors (PARs). Although the role of PARs is well-established in the development and progression of certain types of cancer, their impact on cancer immune response is only just emerging. The present review highlights how coagulation protease-driven PAR signaling plays a key role in modulating innate and adaptive immune responses. This is followed by a detailed discussion on the contribution of coagulation protease-induced signaling in cancer immune evasion, thereby supporting the growth and development of certain tumors. A special section of the review demonstrates the role of coagulation proteases, thrombin, factor VIIa, and factor Xa in cancer immune evasion. Targeting coagulation protease-induced signaling might be a potential therapeutic strategy to boost the immune surveillance mechanism of a host fighting against cancer, thereby augmenting the clinical consequences of targeted immunotherapeutic regimens.

Glioblastoma is an aggressive type of cancer that begins in cells called astrocytes that support nerve cells that can occur in the brain or spinal cord. It can form in the brain or spinal cord. Despite the variety of modern therapies against GBM, it is still a deadly disease. Patients usually have a median survival of approximately 14 to 15 months from the diagnosis. Glioblastoma is also known as glioblastoma multiforme. The pathogenesis contributing to the proliferation and metastasis of cancer involves aberrations of multiple signalling pathways through multiple genetic mutations and altered gene expression. The coagulant factors like thrombin and tissue factor play a noteworthy role in cancer invasion. They are produced in the microenvironment of glioma through activation of protease-activated receptors (PARs) which are activated by coagulation proteases. PARs are members of family G-protein-coupled receptors (GPCRs) that are activated by coagulation proteases. These components play a key role in tumour cell angiogenesis, migration, invasion, and interactions with host vascular cells. Further, the release of neurotransmitters is also found to regulate malignancy in gliomas. Exploration of the interplay between malignant neural circuitry with the normal conditions is also decisive in finding effective therapies for these apparently invasive tumours. The present review discusses the molecular classification of gliomas, activation of PARs by coagulation protease, and its role in metastasis of gliomas. Further, the differential involvement of neurotransmitters in the pathogenesis of gliomas has also been discussed. Targeting these molecules may present a potential therapeutic approach for the treatment of gliomas.