6MUE

Voltage-gated sodium channel NaV1.4 IQ domain in complex with Ca2+/Calmodulin

Summary for 6MUE

• Entry DOI: 10.2210/pdb6mue/pdb
• Related: 6MUD
• Descriptor: Calmodulin-1, Sodium channel protein type 4 subunit alpha, CALCIUM ION, ... (4 entities in total)
• Functional Keywords: voltage-gated ion channel, transport protein, iq domain, calcium binding-transport protein complex, calcium binding/transport protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 20742.25

Authors

Gardill, B.R.,Van Petegem, F. (deposition date: 2018-10-23, release date: 2019-05-08, Last modification date: 2024-11-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.9 Å)