Structural Insights into the Calcium-Mediated Allosteric Transition in the C-Terminal Domain of Calmodulin from Nuclear Magnetic Resonance Measurements.
Kukic, Predrag ; Lundström, Patrik ; Camilloni, Carlo ; Evenäs, Johan ; Akke, Mikael LU
and Vendruscolo, Michele
(2016)
In Biochemistry
55(1).
p.19-28
- Abstract
- Calmodulin is a two-domain signaling protein that becomes activated upon binding cooperatively two pairs of calcium ions, leading to large-scale conformational changes that expose its binding site. Despite significant advances in understanding the structural biology of calmodulin functions, the mechanistic details of the conformational transition between closed and open states have remained unclear. To investigate this transition, we used a combination of molecular dynamics simulations and nuclear magnetic resonance (NMR) experiments on the Ca(2+)-saturated E140Q C-terminal domain variant. Using chemical shift restraints in replica-averaged metadynamics simulations, we obtained a high-resolution structural ensemble consisting of two... (More)
- Calmodulin is a two-domain signaling protein that becomes activated upon binding cooperatively two pairs of calcium ions, leading to large-scale conformational changes that expose its binding site. Despite significant advances in understanding the structural biology of calmodulin functions, the mechanistic details of the conformational transition between closed and open states have remained unclear. To investigate this transition, we used a combination of molecular dynamics simulations and nuclear magnetic resonance (NMR) experiments on the Ca(2+)-saturated E140Q C-terminal domain variant. Using chemical shift restraints in replica-averaged metadynamics simulations, we obtained a high-resolution structural ensemble consisting of two conformational states and validated such an ensemble against three independent experimental data sets, namely, interproton nuclear Overhauser enhancements, (15)N order parameters, and chemical shift differences between the exchanging states. Through a detailed analysis of this structural ensemble and of the corresponding statistical weights, we characterized a calcium-mediated conformational transition whereby the coordination of Ca(2+) by just one oxygen of the bidentate ligand E140 triggers a concerted movement of the two EF-hands that exposes the target binding site. This analysis provides atomistic insights into a possible Ca(2+)-mediated activation mechanism of calmodulin that cannot be achieved from static structures alone or from ensemble NMR measurements of the transition between conformations. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/8506063
- author
- Kukic, Predrag
; Lundström, Patrik
; Camilloni, Carlo
; Evenäs, Johan
; Akke, Mikael
LU
and Vendruscolo, Michele
- organization
- publishing date
- 2016
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Biochemistry
- volume
- 55
- issue
- 1
- pages
- 19 - 28
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- pmid:26618792
- wos:000368323000003
- scopus:84954445505
- pmid:26618792
- ISSN
- 0006-2960
- DOI
- 10.1021/acs.biochem.5b00961
- language
- English
- LU publication?
- yes
- id
- e5b1a6af-8a55-4fe3-aa43-ce055c83c972 (old id 8506063)
- date added to LUP
- 2016-04-01 11:05:21
- date last changed
- 2022-02-10 08:42:19
@article{e5b1a6af-8a55-4fe3-aa43-ce055c83c972,
abstract = {{Calmodulin is a two-domain signaling protein that becomes activated upon binding cooperatively two pairs of calcium ions, leading to large-scale conformational changes that expose its binding site. Despite significant advances in understanding the structural biology of calmodulin functions, the mechanistic details of the conformational transition between closed and open states have remained unclear. To investigate this transition, we used a combination of molecular dynamics simulations and nuclear magnetic resonance (NMR) experiments on the Ca(2+)-saturated E140Q C-terminal domain variant. Using chemical shift restraints in replica-averaged metadynamics simulations, we obtained a high-resolution structural ensemble consisting of two conformational states and validated such an ensemble against three independent experimental data sets, namely, interproton nuclear Overhauser enhancements, (15)N order parameters, and chemical shift differences between the exchanging states. Through a detailed analysis of this structural ensemble and of the corresponding statistical weights, we characterized a calcium-mediated conformational transition whereby the coordination of Ca(2+) by just one oxygen of the bidentate ligand E140 triggers a concerted movement of the two EF-hands that exposes the target binding site. This analysis provides atomistic insights into a possible Ca(2+)-mediated activation mechanism of calmodulin that cannot be achieved from static structures alone or from ensemble NMR measurements of the transition between conformations.}},
author = {{Kukic, Predrag and Lundström, Patrik and Camilloni, Carlo and Evenäs, Johan and Akke, Mikael and Vendruscolo, Michele}},
issn = {{0006-2960}},
language = {{eng}},
number = {{1}},
pages = {{19--28}},
publisher = {{The American Chemical Society (ACS)}},
series = {{Biochemistry}},
title = {{Structural Insights into the Calcium-Mediated Allosteric Transition in the C-Terminal Domain of Calmodulin from Nuclear Magnetic Resonance Measurements.}},
url = {{http://dx.doi.org/10.1021/acs.biochem.5b00961}},
doi = {{10.1021/acs.biochem.5b00961}},
volume = {{55}},
year = {{2016}},
}