Understanding the functional role of membrane confinements in TNF-mediated signaling by multiscale simulations

Abstract

The interaction between TNFα and TNFR1 is essential in maintaining tissue development and immune responses. While TNFR1 is a cell surface receptor, TNFα exists in both soluble and membrane-bound forms. Interestingly, it was found that the activation of TNFR1-mediated signaling pathways is preferentially through the soluble form of TNFα, which can also induce the clustering of TNFR1 on plasma membrane of living cells. We developed a multiscale simulation framework to compare receptor clustering induced by soluble and membrane-bound ligands. Comparing with the freely diffusive soluble ligands, we hypothesize that the conformational dynamics of membrane-bound ligands are restricted, which affects the clustering of ligand-receptor complexes at cell-cell interfaces. Our simulation revealed that only small clusters can form if TNFα is bound on cell surface. In contrast, the clustering triggered by soluble TNFα is more dynamic, and the size of clusters is statistically larger. We therefore demonstrated the impact of membrane-bound ligand on dynamics of receptor clustering. Moreover, considering that larger TNFα-TNFR1 clusters is more likely to provide spatial platform for downstream signaling pathway, our studies offer new mechanistic insights about why the activation of TNFR1-mediated signaling pathways is not preferred by membrane-bound form of TNFα.

Extracellular Vesicle-Associated TWEAK Contributes to Vascular Inflammation and Remodeling During Acute Cellular Rejection

“…It has been posited that the conformational dynamics of membrane-bound TNF are restricted and, therefore, generally less favored to bind to the TNFR1 receptor. 67 The most striking difference seen here is on the release of MIF, where vesicular TWEAK is almost 4-fold more potent than soluble TWEAK. On the other hand, the release of CXCL1 is seen only in the presence of soluble TWEAK.…”

The Role of TNF-α in Alzheimer’s Disease: A Narrative Review

“…Soluble TNF-α functions are mediated through TNFR1 and TNFR2 and, interestingly, it has been shown that TNFR1-mediated signaling pathways predominantly occur via the soluble form of TNFα. Additionally, this soluble form has the capacity to initiate the clustering of TNFR1 on the plasma membrane of living cells [ 40 ].…”

How does the same ligand activate signaling of different receptors in TNFR superfamily: a computational study

“…It was found that the structures of dimeric TNFR are steadier than monomeric receptor and are favored under acidic conditions (Roy 2017, 2019). In our former work, we have further shown that the conformational dynamics of mTNFα can be significantly changed by these constraints which further affect the spatial–temporal features in clustering of TNFR1 relative to the sTNFα system (Su et al 2022). Based on these preliminary studies, here we further hypothesize that while TNFR1 system prefers sTNFα‐induced clustering to membrane‐bound ligands, the clustering of mTNFα‐bound TNFR2 at cell interfaces is more favorable due to the changes of conformational dynamics under membrane confined condition.…”