文章基本信息

标题：Crystal structures of Ca2+–calmodulin bound to NaV C-terminal regions suggest role for EF-hand domain in binding and inactivation
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作者：Bernd R. Gardill ; Bernd R. Gardill ; Ricardo E. Rivera-Acevedo 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2019
卷号：116
期号：22
页码：10763-10772
DOI：10.1073/pnas.1818618116
出版社：The National Academy of Sciences of the United States of America
摘要：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 Ca²⁺-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 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 Na_V1.4 channel has been shown to undergo Ca²⁺-dependent inactivation (CDI) akin to Ca_Vs. We present a crystal structure of Ca²⁺/CaM bound to the Na_V1.4 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.
关键词：sodium channel ; inactivation ; cardiac arrhythmia ; long-QT syndrome ; calcium-dependent inactivation