Structural and Energetic Determinants of Apo Calmodulin Binding to the IQ Motif of the NaV1.2 Voltage-Dependent Sodium Channel

SummaryThe neuronal voltage-dependent sodium channel (Nav1.2), essential for generation and propagation of action potentials, is regulated by calmodulin (CaM) binding to the IQ motif in its α subunit. A peptide (Nav1.2IQp, KRKQEEVSAIVIQRAYRRYLLKQKVKK) representing the IQ motif had higher affinity for apo CaM than (Ca2+)4-CaM. Association was mediated solely by the C-domain of CaM. A solution structure (2KXW.pdb) of apo 13C,15N-CaM C-domain bound to Nav1.2IQp was determined with NMR. The region of Nav1.2IQp bound to CaM was helical; R1902, an Nav1.2 residue implicated in familial autism, did not contact CaM. The apo C-domain of CaM in this complex shares features of the same domain bound to myosin V IQ motifs (2IX7) and bound to an SK channel peptide (1G4Y) that does not contain an IQ motif. Thermodynamic and structural studies of CaM-Nav1.2IQp interactions show that apo and (Ca2+)4-CaM adopt distinct conformations that both permit tight association with Nav1.2IQp during gating