How Does the Same Ligand Activate Signaling of Different Receptors in TNFR Superfamily: a Computational Study

Overview

Journal J Cell Commun Signal

Date 2022 Sep 28

PMID 36167956

Authors

Zhaoqian Su

Yinghao Wu

Affiliations

Soon will be listed here.

Abstract

TNFα is a highly pleiotropic cytokine inducing inflammatory signaling pathways. It is initially presented on plasma membrane of cells (mTNFα), and also exists in a soluble variant (sTNFα) after cleavage. The ligand is shared by two structurally similar receptors, TNFR1 and TNFR2. Interestingly, while sTNFα preferentially stimulates TNFR1, TNFR2 signaling can only be activated by mTNFα. How can two similar receptors respond to the same ligand in such a different way? We employed computational simulations in multiple scales to address this question. We found that both mTNFα and sTNFα can trigger the clustering of TNFR1. The size of clusters induced by sTNFα is constantly larger than the clusters induced by mTNFα. The systems of TNFR2, on the other hand, show very different behaviors. Only when the interactions between TNFR2 are very weak, mTNFα can trigger the receptors to form very large clusters. Given the same weak binding affinity, only small oligomers were obtained in the system of sTNFα. Considering that TNF-mediated signaling is modulated by the ligand-induced clustering of receptors on cell surface, our study provided the mechanistic foundation to the phenomenon that different isoforms of the ligand can lead to highly distinctive signaling patterns for its receptors.

References

Xie P . TRAF molecules in cell signaling and in human diseases. J Mol Signal. 2013; 8(1):7. PMC: 3697994. DOI: 10.1186/1750-2187-8-7. View

Zhang C, Liu S, Zhou H, Zhou Y . An accurate, residue-level, pair potential of mean force for folding and binding based on the distance-scaled, ideal-gas reference state. Protein Sci. 2004; 13(2):400-11. PMC: 2286718. DOI: 10.1110/ps.03348304. View

Aragon S . A precise boundary element method for macromolecular transport properties. J Comput Chem. 2004; 25(9):1191-205. DOI: 10.1002/jcc.20045. View

Aggarwal B, Gupta S, Kim J . Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey. Blood. 2011; 119(3):651-65. PMC: 3265196. DOI: 10.1182/blood-2011-04-325225. View

Grell M, Douni E, Wajant H, Lohden M, Clauss M, Maxeiner B . The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell. 1995; 83(5):793-802. DOI: 10.1016/0092-8674(95)90192-2. View

Lo C, Schaaf T, Grant B, Lim C, Bawaskar P, Aldrich C . Noncompetitive inhibitors of TNFR1 probe conformational activation states. Sci Signal. 2019; 12(592). PMC: 7008598. DOI: 10.1126/scisignal.aav5637. View

Chen S, Feng Z, Wang Y, Ma S, Hu Z, Yang P . Discovery of Novel Ligands for TNF-α and TNF Receptor-1 through Structure-Based Virtual Screening and Biological Assay. J Chem Inf Model. 2017; 57(5):1101-1111. PMC: 6732210. DOI: 10.1021/acs.jcim.6b00672. View

Wang B, Xie Z, Chen J, Wu Y . Integrating Structural Information to Study the Dynamics of Protein-Protein Interactions in Cells. Structure. 2018; 26(10):1414-1424.e3. PMC: 6582366. DOI: 10.1016/j.str.2018.07.010. View

Gumbart J, Roux B, Chipot C . Efficient determination of protein-protein standard binding free energies from first principles. J Chem Theory Comput. 2013; 9(8). PMC: 3809040. DOI: 10.1021/ct400273t. View

10.

Hehlgans T, Pfeffer K . The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: players, rules and the games. Immunology. 2005; 115(1):1-20. PMC: 1782125. DOI: 10.1111/j.1365-2567.2005.02143.x. View

11.

Prada J, Wangorsch G, Kucka K, Lang I, Dandekar T, Wajant H . A systems-biology model of the tumor necrosis factor (TNF) interactions with TNF receptor 1 and 2. Bioinformatics. 2020; 37(5):669-676. DOI: 10.1093/bioinformatics/btaa844. View

12.

Mukai Y, Nakamura T, Yoshikawa M, Yoshioka Y, Tsunoda S, Nakagawa S . Solution of the structure of the TNF-TNFR2 complex. Sci Signal. 2010; 3(148):ra83. DOI: 10.1126/scisignal.2000954. View

13.

Su Z, Dhusia K, Wu Y . Understanding the functional role of membrane confinements in TNF-mediated signaling by multiscale simulations. Commun Biol. 2022; 5(1):228. PMC: 8917213. DOI: 10.1038/s42003-022-03179-1. View

14.

Yang S, Wang J, Brand D, Zheng S . Role of TNF-TNF Receptor 2 Signal in Regulatory T Cells and Its Therapeutic Implications. Front Immunol. 2018; 9:784. PMC: 5916970. DOI: 10.3389/fimmu.2018.00784. View

15.

Chan F, Chun H, Zheng L, Siegel R, Bui K, Lenardo M . A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science. 2000; 288(5475):2351-4. DOI: 10.1126/science.288.5475.2351. View

16.

Naismith J, Devine T, Brandhuber B, Sprang S . Crystallographic evidence for dimerization of unliganded tumor necrosis factor receptor. J Biol Chem. 1995; 270(22):13303-7. DOI: 10.1074/jbc.270.22.13303. View

17.

Lalli E, Sassone-Corsi P . Signal transduction and gene regulation: the nuclear response to cAMP. J Biol Chem. 1994; 269(26):17359-62. View

18.

Dustin M, Bromley S, Davis M, Zhu C . Identification of self through two-dimensional chemistry and synapses. Annu Rev Cell Dev Biol. 2001; 17:133-57. DOI: 10.1146/annurev.cellbio.17.1.133. View

19.

Krauss R . Regulation of promyogenic signal transduction by cell-cell contact and adhesion. Exp Cell Res. 2010; 316(18):3042-9. PMC: 2945434. DOI: 10.1016/j.yexcr.2010.05.008. View

20.

McMillan D, Martinez-Fleites C, Porter J, Fox 3rd D, Davis R, Mori P . Structural insights into the disruption of TNF-TNFR1 signalling by small molecules stabilising a distorted TNF. Nat Commun. 2021; 12(1):582. PMC: 7835368. DOI: 10.1038/s41467-020-20828-3. View