Conformational heterogeneity of the calmodulin binding interface
Calmodulin (CaM) is a ubiquitous Ca2+ sensor and a crucial signalling hub in many pathways aberrantly activated in disease. However, the mechanistic basis of its ability to bind diverse signalling molecules including G-protein-coupled receptors, ion channels and kinases remains poorly understood. He...
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Nature Publishing Group
2016
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822001/ |
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pubmed-48220012016-04-17 Conformational heterogeneity of the calmodulin binding interface Shukla, Diwakar Peck, Ariana Pande, Vijay S. Article Calmodulin (CaM) is a ubiquitous Ca2+ sensor and a crucial signalling hub in many pathways aberrantly activated in disease. However, the mechanistic basis of its ability to bind diverse signalling molecules including G-protein-coupled receptors, ion channels and kinases remains poorly understood. Here we harness the high resolution of molecular dynamics simulations and the analytical power of Markov state models to dissect the molecular underpinnings of CaM binding diversity. Our computational model indicates that in the absence of Ca2+, sub-states in the folded ensemble of CaM's C-terminal domain present chemically and sterically distinct topologies that may facilitate conformational selection. Furthermore, we find that local unfolding is off-pathway for the exchange process relevant for peptide binding, in contrast to prior hypotheses that unfolding might account for binding diversity. Finally, our model predicts a novel binding interface that is well-populated in the Ca2+-bound regime and, thus, a candidate for pharmacological intervention. Nature Publishing Group 2016-04-04 /pmc/articles/PMC4822001/ /pubmed/27040077 http://dx.doi.org/10.1038/ncomms10910 Text en Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Shukla, Diwakar Peck, Ariana Pande, Vijay S. |
| spellingShingle |
Shukla, Diwakar Peck, Ariana Pande, Vijay S. Conformational heterogeneity of the calmodulin binding interface |
| author_facet |
Shukla, Diwakar Peck, Ariana Pande, Vijay S. |
| author_sort |
Shukla, Diwakar |
| title |
Conformational heterogeneity of the calmodulin binding interface |
| title_short |
Conformational heterogeneity of the calmodulin binding interface |
| title_full |
Conformational heterogeneity of the calmodulin binding interface |
| title_fullStr |
Conformational heterogeneity of the calmodulin binding interface |
| title_full_unstemmed |
Conformational heterogeneity of the calmodulin binding interface |
| title_sort |
conformational heterogeneity of the calmodulin binding interface |
| description |
Calmodulin (CaM) is a ubiquitous Ca2+ sensor and a crucial signalling hub in many pathways aberrantly activated in disease. However, the mechanistic basis of its ability to bind diverse signalling molecules including G-protein-coupled receptors, ion channels and kinases remains poorly understood. Here we harness the high resolution of molecular dynamics simulations and the analytical power of Markov state models to dissect the molecular underpinnings of CaM binding diversity. Our computational model indicates that in the absence of Ca2+, sub-states in the folded ensemble of CaM's C-terminal domain present chemically and sterically distinct topologies that may facilitate conformational selection. Furthermore, we find that local unfolding is off-pathway for the exchange process relevant for peptide binding, in contrast to prior hypotheses that unfolding might account for binding diversity. Finally, our model predicts a novel binding interface that is well-populated in the Ca2+-bound regime and, thus, a candidate for pharmacological intervention. |
| publisher |
Nature Publishing Group |
| publishDate |
2016 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822001/ |
| _version_ |
1613562726478512128 |