TY - JOUR
T1 - A computational model for understanding the oligomerization mechanisms of TNF receptor superfamily
AU - Su, Zhaoqian
AU - Wu, Yinghao
N1 - Funding Information:
This work was supported by the National Institutes of Health under Grant Numbers R01GM122804 . The work is also partially supported by a start-up grant from Albert Einstein College of Medicine . Computational support was provided by Albert Einstein College of Medicine High Performance Computing Center.
Funding Information:
This work was supported by the National Institutes of Health under Grant Numbers R01GM122804. The work is also partially supported by a start-up grant from Albert Einstein College of Medicine. Computational support was provided by Albert Einstein College of Medicine High Performance Computing Center. Z.S and Y.W. designed research; Z.S. performed research; Z.S. and Y.W. analyzed data; Z.S. and Y.W. wrote the paper.
Publisher Copyright:
© 2020 The Authors
PY - 2020
Y1 - 2020
N2 - By recognizing members in the tumor necrosis factor (TNF) receptor superfamily, TNF ligand proteins function as extracellular cytokines to activate various signaling pathways involved in inflammation, proliferation, and apoptosis. Most ligands in TNF superfamily are trimeric and can simultaneously bind to three receptors on cell surfaces. It has been experimentally observed that the formation of these molecular complexes further triggers the oligomerization of TNF receptors, which in turn regulate the intracellular signaling processes by providing transient compartmentalization in the membrane proximal regions of cytoplasm. In order to decode the molecular mechanisms of oligomerization in TNF receptor superfamily, we developed a new computational method that can physically simulate the spatial-temporal process of binding between TNF ligands and their receptors. The simulations show that the TNF receptors can be organized into hexagonal oligomers. The formation of this spatial pattern is highly dependent not only on the molecular properties such as the affinities of trans and cis binding, but also on the cellular factors such as the concentration of TNF ligands in the extracellular area or the density of TNF receptors on cell surfaces. Moreover, our model suggests that if TNF receptors are pre-organized into dimers before ligand binding, these lateral interactions between receptor monomers can play a positive role in stabilizing the ligand-receptor interactions, as well as in regulating the kinetics of receptor oligomerization. Altogether, this method throws lights on the mechanisms of TNF ligand-receptor interactions in cellular environments.
AB - By recognizing members in the tumor necrosis factor (TNF) receptor superfamily, TNF ligand proteins function as extracellular cytokines to activate various signaling pathways involved in inflammation, proliferation, and apoptosis. Most ligands in TNF superfamily are trimeric and can simultaneously bind to three receptors on cell surfaces. It has been experimentally observed that the formation of these molecular complexes further triggers the oligomerization of TNF receptors, which in turn regulate the intracellular signaling processes by providing transient compartmentalization in the membrane proximal regions of cytoplasm. In order to decode the molecular mechanisms of oligomerization in TNF receptor superfamily, we developed a new computational method that can physically simulate the spatial-temporal process of binding between TNF ligands and their receptors. The simulations show that the TNF receptors can be organized into hexagonal oligomers. The formation of this spatial pattern is highly dependent not only on the molecular properties such as the affinities of trans and cis binding, but also on the cellular factors such as the concentration of TNF ligands in the extracellular area or the density of TNF receptors on cell surfaces. Moreover, our model suggests that if TNF receptors are pre-organized into dimers before ligand binding, these lateral interactions between receptor monomers can play a positive role in stabilizing the ligand-receptor interactions, as well as in regulating the kinetics of receptor oligomerization. Altogether, this method throws lights on the mechanisms of TNF ligand-receptor interactions in cellular environments.
KW - Kinetic Monte-Carlo simulation
KW - Receptor oligomerization
KW - Tumor necrosis factor
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U2 - 10.1016/j.csbj.2019.12.016
DO - 10.1016/j.csbj.2019.12.016
M3 - Article
AN - SCOPUS:85078459067
VL - 18
SP - 258
EP - 270
JO - Computational and Structural Biotechnology Journal
JF - Computational and Structural Biotechnology Journal
SN - 2001-0370
ER -