6MUD

Voltage-gated sodium channel NaV1.5 C-terminal domain in complex with Ca2+/Calmodulin

6MUD の概要

• エントリーDOI: 10.2210/pdb6mud/pdb
• 分子名称: Calmodulin-1, Sodium channel protein type 5 subunit alpha, CALCIUM ION, ... (4 entities in total)
• 機能のキーワード: voltage-gated ion channel, transport protein, ef-hand domain, calcium binding-transport protein complex, calcium binding/transport protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 33270.51

構造登録者

Gardill, B.R.,Tung, C.C.,Van Petegem, F. (登録日: 2018-10-23, 公開日: 2019-05-08, 最終更新日: 2024-03-13)

主引用文献

Gardill, B.R.,Rivera-Acevedo, R.E.,Tung, C.C.,Van Petegem, F.
Crystal structures of Ca2+-calmodulin bound to NaVC-terminal regions suggest role for EF-hand domain in binding and inactivation.
Proc.Natl.Acad.Sci.USA, 116:10763-10772, 2019

PubMed Abstract: Voltage-gated sodium (Na) and calcium channels (Ca) 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-occupied CaM, bound to the CT of Na1.5. 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 Na1.5 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-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-free and Ca-occupied CaM contain targets for mutations linked to long-QT syndrome, a type of inherited arrhythmia. The related Na1.4 channel has been shown to undergo Ca-dependent inactivation (CDI) akin to Cas. We present a crystal structure of Ca/CaM bound to the Na1.4 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.

PubMed: 31072926
DOI: 10.1073/pnas.1818618116

実験手法

X-RAY DIFFRACTION (2.69 Å)