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A multiscale study on the mechanisms of spatial organization in ligand-receptor interactions on cell surfaces

Authors :
Zhaoqian Su
Kalyani Dhusia
Yinghao Wu
Source :
Computational and Structural Biotechnology Journal, Vol 19, Iss , Pp 1620-1634 (2021)
Publication Year :
2021
Publisher :
Elsevier, 2021.

Abstract

The binding of cell surface receptors with extracellular ligands triggers distinctive signaling pathways, leading into the corresponding phenotypic variation of cells. It has been found that in many systems, these ligand-receptor complexes can further oligomerize into higher-order structures. This ligand-induced oligomerization of receptors on cell surfaces plays an important role in regulating the functions of cell signaling. The underlying mechanism, however, is not well understood. One typical example is proteins that belong to the tumor necrosis factor receptor (TNFR) superfamily. Using a generic multiscale simulation platform that spans from atomic to subcellular levels, we compared the detailed physical process of ligand-receptor oligomerization for two specific members in the TNFR superfamily: the complex formed between ligand TNFα and receptor TNFR1 versus the complex formed between ligand TNFβ and receptor TNFR2. Interestingly, although these two systems share high similarity on the tertiary and quaternary structural levels, our results indicate that their oligomers are formed with very different dynamic properties and spatial patterns. We demonstrated that the changes of receptor’s conformational fluctuations due to the membrane confinements are closely related to such difference. Consistent to previous experiments, our simulations also showed that TNFR can preassemble into dimers prior to ligand binding, while the introduction of TNF ligands induced higher-order oligomerization due to a multivalent effect. This study, therefore, provides the molecular basis to TNFR oligomerization and reveals new insights to TNFR-mediated signal transduction. Moreover, our multiscale simulation framework serves as a prototype that paves the way to study higher-order assembly of cell surface receptors in many other bio-systems.

Details

Language :
English
ISSN :
20010370
Volume :
19
Issue :
1620-1634
Database :
Directory of Open Access Journals
Journal :
Computational and Structural Biotechnology Journal
Publication Type :
Academic Journal
Accession number :
edsdoj.116136fe356c4098bbb3a520d46c402d
Document Type :
article
Full Text :
https://doi.org/10.1016/j.csbj.2021.03.024