4DJC

1.35 A crystal structure of the NaV1.5 DIII-IV-Ca/CaM complex

4DJC の概要

• エントリーDOI: 10.2210/pdb4djc/pdb
• 分子名称: Calmodulin, Sodium channel protein type 5 subunit alpha, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: ef-hand, calcium-binding protein
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Cell membrane ; Multi-pass membrane protein : Q14524
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 21947.88

構造登録者

Sarhan, M.F.,Tung, C.-C.,Van Petegem, F.,Ahern, C.A. (登録日: 2012-02-01, 公開日: 2012-02-22, 最終更新日: 2024-02-28)

主引用文献

Sarhan, M.F.,Tung, C.C.,Van Petegem, F.,Ahern, C.A.
Crystallographic basis for calcium regulation of sodium channels.
Proc.Natl.Acad.Sci.USA, 109:3558-3563, 2012

PubMed Abstract: Voltage-gated sodium channels underlie the rapid regenerative upstroke of action potentials and are modulated by cytoplasmic calcium ions through a poorly understood mechanism. We describe the 1.35 Å crystal structure of Ca(2+)-bound calmodulin (Ca(2+)/CaM) in complex with the inactivation gate (DIII-IV linker) of the cardiac sodium channel (Na(V)1.5). The complex harbors the positions of five disease mutations involved with long Q-T type 3 and Brugada syndromes. In conjunction with isothermal titration calorimetry, we identify unique inactivation-gate mutations that enhance or diminish Ca(2+)/CaM binding, which, in turn, sensitize or abolish Ca(2+) regulation of full-length channels in electrophysiological experiments. Additional biochemical experiments support a model whereby a single Ca(2+)/CaM bridges the C-terminal IQ motif to the DIII-IV linker via individual N and C lobes, respectively. The data suggest that Ca(2+)/CaM destabilizes binding of the inactivation gate to its receptor, thus biasing inactivation toward more depolarized potentials.

PubMed: 22331908
DOI: 10.1073/pnas.1114748109

実験手法

X-RAY DIFFRACTION (1.35 Å)