MHC binding affects the dynamics of different T-cell receptors in different ways

Autor: Charlotte M. Deane, Bernhard Knapp, P. Anton van der Merwe, Omer Dushek
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Cell signaling
Protein Conformation
Plasma protein binding
Immune Receptors
Biochemistry
Major Histocompatibility Complex
White Blood Cells
0302 clinical medicine
Protein structure
Animal Cells
Histocompatibility Antigens
Medicine and Health Sciences
Biochemical Simulations
Macromolecular Structure Analysis
Biology (General)
Receptor
Immune System Proteins
Ecology
biology
TCR signaling cascade
Chemistry
T Cells
Simulation and Modeling
Signaling cascades
hemic and immune systems
Cell biology
medicine.anatomical_structure
Computational Theory and Mathematics
Modeling and Simulation
Physical Sciences
Signal transduction
Cellular Types
Research Article
Signal Transduction
Protein Binding
Protein Structure
QH301-705.5
Permutation
T cell
Immune Cells
Allosteric regulation
Immunology
Receptors
Antigen
T-Cell
chemical and pharmacologic phenomena
Molecular Dynamics Simulation
Major histocompatibility complex
Research and Analysis Methods
03 medical and health sciences
Cellular and Molecular Neuroscience
Genetics
medicine
Humans
Molecular Biology
Ecology
Evolution
Behavior and Systematics
Blood Cells
Discrete Mathematics
T-cell receptor
Biology and Life Sciences
Proteins
Computational Biology
Cell Biology
T Cell Receptors
030104 developmental biology
Combinatorics
biology.protein
Clinical Immunology
Clinical Medicine
030217 neurology & neurosurgery
Mathematics
Zdroj: PLoS Computational Biology
PLoS Computational Biology, Vol 15, Iss 9, p e1007338 (2019)
ISSN: 1553-7358
1553-734X
Popis: T cells use their T-cell receptors (TCRs) to scan other cells for antigenic peptides presented by MHC molecules (pMHC). If a TCR encounters a pMHC, it can trigger a signalling pathway that could lead to the activation of the T cell and the initiation of an immune response. It is currently not clear how the binding of pMHC to the TCR initiates signalling within the T cell. One hypothesis is that conformational changes in the TCR lead to further downstream signalling. Here we investigate four different TCRs in their free state as well as in their pMHC bound state using large scale molecular simulations totalling 26 000 ns. We find that the dynamical features within TCRs differ significantly between unbound TCR and TCR/pMHC simulations. However, apart from expected results such as reduced solvent accessibility and flexibility of the interface residues, these features are not conserved among different TCR types. The presence of a pMHC alone is not sufficient to cause cross-TCR-conserved dynamical features within a TCR. Our results argue against models of TCR triggering involving conserved allosteric conformational changes.
Author summary The interaction between T-cells and other cells is one of the most important interactions in the human immune system. If T-cells are not triggered major parts of the immune system cannot be activated or are not working effectively. Despite many years of research the exact mechanism of how a T-cell is initially triggered is not clear. One hypothesis is that conformational changes within the T-cell receptor (TCR) can cause further downstream signalling within the T-cell. In this study we computationally investigate the dynamics of four different TCRs in their free and bound configuration. Our large scale simulations show that all four TCRs react to binding in different ways. In some TCRs mainly the areas close to the binding region are affected while in other TCRs areas further apart from the binding region are also affected. Our results argue against a conserved structural activation mechanism across different types of TCRs.
Databáze: OpenAIRE
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