Structural and energetic determinants of apo calmodulin binding to the IQ motif of the Na V1.2 voltage-dependent sodium channel

Abstract

The neuronal voltage-dependent sodium channel (Na v1.2), essential for generation and propagation of action potentials, is regulated by calmodulin (CaM) binding to the IQ motif in its α subunit. A peptide (Na v1.2 IQp, KRKQEEVSAIVIQRAYRRYLLKQKVKK) representing the IQ motif had higher affinity for apo CaM than (Ca 2+) 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 Na v1.2 IQp was determined with NMR. The region of Na v1.2 IQp bound to CaM was helical; R1902, an Na v1.2 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-Na v1.2 IQp interactions show that apo and (Ca 2+) 4-CaM adopt distinct conformations that both permit tight association with Na v1.2 IQp during gating. © 2011 Elsevier Ltd All rights reserved.