Cargando…
A Common Model for Cytokine Receptor Activation: Combined Scissor-Like Rotation and Self-Rotation of Receptor Dimer Induced by Class I Cytokine
The precise mechanism by which the binding of a class I cytokine to the extracellular domain of its corresponding receptor transmits a signal through the cell membrane remains unclear. Receptor activation involves a cytokine-receptor complex with a 1∶2 stoichiometry. Previously we used our transient...
Autores principales: | , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297564/ https://www.ncbi.nlm.nih.gov/pubmed/22412367 http://dx.doi.org/10.1371/journal.pcbi.1002427 |
_version_ | 1782225888943800320 |
---|---|
author | Pang, Xiaodong Zhou, Huan-Xiang |
author_facet | Pang, Xiaodong Zhou, Huan-Xiang |
author_sort | Pang, Xiaodong |
collection | PubMed |
description | The precise mechanism by which the binding of a class I cytokine to the extracellular domain of its corresponding receptor transmits a signal through the cell membrane remains unclear. Receptor activation involves a cytokine-receptor complex with a 1∶2 stoichiometry. Previously we used our transient-complex theory to calculate the rate constant of the initial cytokine-receptor binding to form a 1∶1 complex. Here we computed the binding pathway leading to the 1∶2 activation complex. Three cytokine systems (growth hormone, erythropoietin, and prolactin) were studied, and the focus was on the binding of the extracellular domain of the second receptor molecule after forming the 1∶1 complex. According to the transient-complex theory, translational and rotation diffusion of the binding entities bring them together to form a transient complex, which has near-native relative separation and orientation but not the short-range specific native interactions. Subsequently conformational rearrangement leads to the formation of the native complex. We found that the changes in relative orientations between the two receptor molecules from the transient complex to the 1∶2 native complex are similar for the three cytokine-receptor systems. We thus propose a common model for receptor activation by class I cytokines, involving combined scissor-like rotation and self-rotation of the two receptor molecules. Both types of rotations seem essential: the scissor-like rotation separates the intracellular domains of the two receptor molecules to make room for the associated Janus kinase molecules, while the self-rotation allows them to orient properly for transphosphorylation. This activation model explains a host of experimental observations. The transient-complex based approach presented here may provide a strategy for designing antagonists and prove useful for elucidating activation mechanisms of other receptors. |
format | Online Article Text |
id | pubmed-3297564 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-32975642012-03-12 A Common Model for Cytokine Receptor Activation: Combined Scissor-Like Rotation and Self-Rotation of Receptor Dimer Induced by Class I Cytokine Pang, Xiaodong Zhou, Huan-Xiang PLoS Comput Biol Research Article The precise mechanism by which the binding of a class I cytokine to the extracellular domain of its corresponding receptor transmits a signal through the cell membrane remains unclear. Receptor activation involves a cytokine-receptor complex with a 1∶2 stoichiometry. Previously we used our transient-complex theory to calculate the rate constant of the initial cytokine-receptor binding to form a 1∶1 complex. Here we computed the binding pathway leading to the 1∶2 activation complex. Three cytokine systems (growth hormone, erythropoietin, and prolactin) were studied, and the focus was on the binding of the extracellular domain of the second receptor molecule after forming the 1∶1 complex. According to the transient-complex theory, translational and rotation diffusion of the binding entities bring them together to form a transient complex, which has near-native relative separation and orientation but not the short-range specific native interactions. Subsequently conformational rearrangement leads to the formation of the native complex. We found that the changes in relative orientations between the two receptor molecules from the transient complex to the 1∶2 native complex are similar for the three cytokine-receptor systems. We thus propose a common model for receptor activation by class I cytokines, involving combined scissor-like rotation and self-rotation of the two receptor molecules. Both types of rotations seem essential: the scissor-like rotation separates the intracellular domains of the two receptor molecules to make room for the associated Janus kinase molecules, while the self-rotation allows them to orient properly for transphosphorylation. This activation model explains a host of experimental observations. The transient-complex based approach presented here may provide a strategy for designing antagonists and prove useful for elucidating activation mechanisms of other receptors. Public Library of Science 2012-03-08 /pmc/articles/PMC3297564/ /pubmed/22412367 http://dx.doi.org/10.1371/journal.pcbi.1002427 Text en Pang, Zhou. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Pang, Xiaodong Zhou, Huan-Xiang A Common Model for Cytokine Receptor Activation: Combined Scissor-Like Rotation and Self-Rotation of Receptor Dimer Induced by Class I Cytokine |
title | A Common Model for Cytokine Receptor Activation: Combined Scissor-Like Rotation and Self-Rotation of Receptor Dimer Induced by Class I Cytokine |
title_full | A Common Model for Cytokine Receptor Activation: Combined Scissor-Like Rotation and Self-Rotation of Receptor Dimer Induced by Class I Cytokine |
title_fullStr | A Common Model for Cytokine Receptor Activation: Combined Scissor-Like Rotation and Self-Rotation of Receptor Dimer Induced by Class I Cytokine |
title_full_unstemmed | A Common Model for Cytokine Receptor Activation: Combined Scissor-Like Rotation and Self-Rotation of Receptor Dimer Induced by Class I Cytokine |
title_short | A Common Model for Cytokine Receptor Activation: Combined Scissor-Like Rotation and Self-Rotation of Receptor Dimer Induced by Class I Cytokine |
title_sort | common model for cytokine receptor activation: combined scissor-like rotation and self-rotation of receptor dimer induced by class i cytokine |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297564/ https://www.ncbi.nlm.nih.gov/pubmed/22412367 http://dx.doi.org/10.1371/journal.pcbi.1002427 |
work_keys_str_mv | AT pangxiaodong acommonmodelforcytokinereceptoractivationcombinedscissorlikerotationandselfrotationofreceptordimerinducedbyclassicytokine AT zhouhuanxiang acommonmodelforcytokinereceptoractivationcombinedscissorlikerotationandselfrotationofreceptordimerinducedbyclassicytokine AT pangxiaodong commonmodelforcytokinereceptoractivationcombinedscissorlikerotationandselfrotationofreceptordimerinducedbyclassicytokine AT zhouhuanxiang commonmodelforcytokinereceptoractivationcombinedscissorlikerotationandselfrotationofreceptordimerinducedbyclassicytokine |