Highlights
Resting membrane potential determines the excitability of the cell and is essential for the cellular electrical activities
FAM155 is the homolog of NLF-1 in C. elegans, which is required for the membrane localization of NALCN12
Because NALCN protein dictates the properties of ion permeation, divalent ion block and voltage modulation[1] and FAM155 are required for correct trafficking of NALCN12, we reasoned the structure of NALCN–FAM155A complex would provide clues of how NALCN channel works
Summary
Resting membrane potential determines the excitability of the cell and is essential for the cellular electrical activities. We find that the noncanonical architecture of NALCN selectivity filter dictates its sodium selectivity and calcium block, and that the asymmetric arrangement of two functional voltage sensors confers the modulation by membrane potential. Residues in the selectivity filter of NALCN are “EEKE” instead of “DEKA” of NaV or “EEEE” of CaV These features render NALCN to be a special clade in the voltage-gated channel superfamily[11]. The coexpression of NALCN, FAM155, UNC79, and UNC80 proteins in a heterologous expression system, such as Xenopus laevis oocytes or HEK293 cells, is necessary and sufficient to generate robust voltage-modulated sodium-selective currents[1]. We describe the structure of rat NALCN and mouse FAM155A in detergent to the resolution of 2.7 Å, which provides enhanced details and additional structural insights into the mechanism of this important channel complex
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