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Fibronectin containing alternatively spliced extra domain A interacts at the central and c-terminal domain of Toll-like receptor-4.

ABSTRACT: Extra domain A of cellular fibronectin (FN-EDA) is known to cause insulin resistance, atherosclerosis, tissue fibrosis, ischemic stroke and exaggerated myocardial reperfusion injury through Toll-like receptor 4 (TLR4). However, the FN-EDA-TLR4 interacting site is not well established. Therefore, in-silico approaches have been used to study FN-EDA and TLR4 interactions at the interface. In the present study, molecular docking studies of FN-EDA with TLR4-myeloid differentiation factor 2 (MD2) heterodimer have been performed to unravel the FN-EDA-TLR4 interacting sequence. Furthermore, the modulatory role of FN-EDA adjacent domains FNIII(11) and FNIII(12) on its interaction with TLR4-MD2 was investigated. The results show that FN-EDA interacting sequence "SPEDGIRELF" selectively interacts with TLR4 directly near its central and C-terminal domain region. The regulatory domains, FN type III 11 facilitate and 12 impede the FN-EDA-TLR4 interaction. Furthermore, the molecular dynamic simulation studies confirmed that FN-EDA forms a stable complex with TLR4-MD2 heterodimer. In conclusion, FN-EDA interacts and forms a stable complex through its "SPEDGIRELF" sequence at the central and C-terminal domain region of TLR4. The revelation of FN-EDA and TLR4 interacting sites may help design novel therapeutics for drug discovery research.

SUBMITTER: Gupta S

PROVIDER: S-EPMC9188610 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Fibronectin containing alternatively spliced extra domain A interacts at the central and c-terminal domain of Toll-like receptor-4.

Gupta Shubhangi S Ali Azeem A Pandey Saurabh S Khan Imran A IA Prakash Prem P

Scientific reports 20220611 1

Extra domain A of cellular fibronectin (FN-EDA) is known to cause insulin resistance, atherosclerosis, tissue fibrosis, ischemic stroke and exaggerated myocardial reperfusion injury through Toll-like receptor 4 (TLR4). However, the FN-EDA-TLR4 interacting site is not well established. Therefore, in-silico approaches have been used to study FN-EDA and TLR4 interactions at the interface. In the present study, molecular docking studies of FN-EDA with TLR4-myeloid differentiation factor 2 (MD2) hete ...[more]

PMID: 35690624

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Project description:BackgroundThe suppression of chimeric antigen receptor (CAR) T cells by the tumor microenvironment (TME) is a crucial obstacle in the T-cell-based treatment of solid tumors. Extra domain B (EDB)-fibronectin is an oncofetal antigen expressed on the endothelium layer of the neovasculature and cancer cells. Though recognized as a T cell therapy target, engineered CAR T cells thus far have failed to demonstrate satisfactory in vivo efficacy. In this study, we report that targeting EDB-fibronectin by redirected TCR-CAR T cells (rTCR-CAR) bypasses the suppressive TME for solid tumor treatment and sufficiently suppressed tumor growth.We generated EDB-targeting CAR by fusing single-chain variable fragment to CD3ε, resulting in rTCR-CAR. Human primary T cells and Jurkat cells were used to study the EDB-targeting T cells. Differences to the traditional second-generation CAR T cell in signaling, immune synapse formation, and T cell exhaustion were characterized. Cytotoxicity of the rTCR-CAR T cells was tested in vitro, and therapeutic efficacies were demonstrated using xenograft models.MethodsRESULTS: In the xenograft models, the rTCR-CAR T cells demonstrated in vivo efficacies superior to that based on traditional CAR design. A significant reduction in tumor vessel density was observed alongside tumor growth inhibition, extending even to tumor models established with EDB-negative cancer cells. The rTCR-CAR bound to immobilized EDB, and the binding led to immune synapse structures superior to that formed by second-generation CARs. By a mechanism similar to that for the conventional TCR complex, EDB-fibronectin activated the rTCR-CAR, resulting in rTCR-CAR T cells with low basal activation levels and increased in vivo expansion.ConclusionOur study has demonstrated the potential of rTCR-CAR T cells targeting the EDB-fibronectin as an anticancer therapeutic. Engineered to possess antiangiogenic and cytotoxic activities, the rTCR-CAR T cells showed therapeutic efficacies not impacted by the suppressive TMEs. These combined characteristics of a single therapeutic agent point to its potential to achieve sustained control of solid tumors.

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Fibronectin containing alternatively spliced extra domain A interacts at the central and c-terminal domain of Toll-like receptor-4.

Publications

Fibronectin containing alternatively spliced extra domain A interacts at the central and c-terminal domain of Toll-like receptor-4.

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