4DJC

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

Summary for 4DJC

• Entry DOI: 10.2210/pdb4djc/pdb
• Descriptor: Calmodulin, Sodium channel protein type 5 subunit alpha, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: ef-hand, calcium-binding protein
• Biological source: Homo sapiens (human); More
• Cellular location: Cell membrane ; Multi-pass membrane protein : Q14524
• Total number of polymer chains: 2
• Total formula weight: 21947.88

Authors

Sarhan, M.F.,Tung, C.-C.,Van Petegem, F.,Ahern, C.A. (deposition date: 2012-02-01, release date: 2012-02-22, Last modification date: 2024-02-28)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.35 Å)