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Title: Crystal structures of Ca 2+–calmodulin bound to Na V C-terminal regions suggest role for EF-hand domain in binding and inactivation

Abstract

Voltage-gated sodium (Na V) and calcium channels (Ca V) form targets for calmodulin (CaM), which affects channel inactivation properties. A major interaction site for CaM resides in the C-terminal (CT) region, consisting of an IQ domain downstream of an EF-hand domain. We present a crystal structure of fully Ca 2+-occupied CaM, bound to the CT of Na V1.5. The structure shows that the C-terminal lobe binds to a site ~90° rotated relative to a previous site reported for an apoCaM complex with the Na V1.5 CT and for ternary complexes containing fibroblast growth factor homologous factors (FHF). We show that the binding of FHFs forces the EF-hand domain in a conformation that does not allow binding of the Ca 2+-occupied C-lobe of CaM. These observations highlight the central role of the EF-hand domain in modulating the binding mode of CaM. The binding sites for Ca 2+-free and Ca 2+-occupied CaM contain targets for mutations linked to long-QT syndrome, a type of inherited arrhythmia. The related Na V1.4 channel has been shown to undergo Ca 2+-dependent inactivation (CDI) akin to Ca Vs. We present a crystal structure of Ca 2+/CaM bound to the Na V1.4 IQ domain, which shows a bindingmore » mode that would clash with the EF-hand domain. We postulate the relative reorientation of the EF-hand domain and the IQ domain as a possible conformational switch that underlies CDI.« less

Authors:
 [1];  [1];  [1]; ORCiD logo [1]
  1. Univ. of British Columbia, Vancouver, BC (Canada)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE; Canadian Institutes of Health Research (CIHR)
OSTI Identifier:
1530994
Grant/Contract Number:  
MOP-119404
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 116; Journal Issue: 22; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; sodium channel; inactivation; cardiac arrhythmia; long-QT syndrome; calcium-dependent inactivation

Citation Formats

Gardill, Bernd R., Rivera-Acevedo, Ricardo E., Tung, Ching-Chieh, and Van Petegem, Filip. Crystal structures of Ca2+–calmodulin bound to NaV C-terminal regions suggest role for EF-hand domain in binding and inactivation. United States: N. p., 2019. Web. doi:10.1073/pnas.1818618116.
Gardill, Bernd R., Rivera-Acevedo, Ricardo E., Tung, Ching-Chieh, & Van Petegem, Filip. Crystal structures of Ca2+–calmodulin bound to NaV C-terminal regions suggest role for EF-hand domain in binding and inactivation. United States. doi:10.1073/pnas.1818618116.
Gardill, Bernd R., Rivera-Acevedo, Ricardo E., Tung, Ching-Chieh, and Van Petegem, Filip. Thu . "Crystal structures of Ca2+–calmodulin bound to NaV C-terminal regions suggest role for EF-hand domain in binding and inactivation". United States. doi:10.1073/pnas.1818618116. https://www.osti.gov/servlets/purl/1530994.
@article{osti_1530994,
title = {Crystal structures of Ca2+–calmodulin bound to NaV C-terminal regions suggest role for EF-hand domain in binding and inactivation},
author = {Gardill, Bernd R. and Rivera-Acevedo, Ricardo E. and Tung, Ching-Chieh and Van Petegem, Filip},
abstractNote = {Voltage-gated sodium (NaV) and calcium channels (CaV) form targets for calmodulin (CaM), which affects channel inactivation properties. A major interaction site for CaM resides in the C-terminal (CT) region, consisting of an IQ domain downstream of an EF-hand domain. We present a crystal structure of fully Ca2+-occupied CaM, bound to the CT of NaV1.5. The structure shows that the C-terminal lobe binds to a site ~90° rotated relative to a previous site reported for an apoCaM complex with the NaV1.5 CT and for ternary complexes containing fibroblast growth factor homologous factors (FHF). We show that the binding of FHFs forces the EF-hand domain in a conformation that does not allow binding of the Ca2+-occupied C-lobe of CaM. These observations highlight the central role of the EF-hand domain in modulating the binding mode of CaM. The binding sites for Ca2+-free and Ca2+-occupied CaM contain targets for mutations linked to long-QT syndrome, a type of inherited arrhythmia. The related NaV1.4 channel has been shown to undergo Ca2+-dependent inactivation (CDI) akin to CaVs. We present a crystal structure of Ca2+/CaM bound to the NaV1.4 IQ domain, which shows a binding mode that would clash with the EF-hand domain. We postulate the relative reorientation of the EF-hand domain and the IQ domain as a possible conformational switch that underlies CDI.},
doi = {10.1073/pnas.1818618116},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
issn = {0027-8424},
number = 22,
volume = 116,
place = {United States},
year = {2019},
month = {5}
}

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