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From Proteopedia
Solution structure of full-length apo mammalian calmodulin bound to the IQ motif of the human voltage-gated sodium channel NaV1.2
Structural highlights
Disease[CALM1_HUMAN] The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM1 are the cause of CPVT4. The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM1 are the cause of LQT14. [SCN2A_HUMAN] Defects in SCN2A are the cause of seizures, benign familial infantile type 3 (BFIS3) [MIM:607745]. An autosomal dominant disorder in which afebrile seizures occur in clusters during the first year of life, without neurologic sequelae.[1] [2] [3] [4] Defects in SCN2A are the cause of epileptic encephalopathy early infantile type 11 (EIEE11) [MIM:613721]. EIEE11 is an autosomal dominant seizure disorder characterized by infantile onset of refractory seizures with resultant delayed neurologic development and persistent neurologic abnormalities.[5] [6] Function[CALM1_HUMAN] Calmodulin mediates the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding. Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases and phosphatases. Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis (PubMed:16760425). Mediates calcium-dependent inactivation of CACNA1C (PubMed:26969752). Positively regulates calcium-activated potassium channel activity of KCNN2 (PubMed:27165696).[7] [8] [9] [10] [SCN2A_HUMAN] Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. Publication Abstract from PubMedHuman voltage-gated sodium channel NaV1.2 has a single pore-forming alpha-subunit and two transmembrane beta-subunits. Expressed primarily in the brain, NaV1.2 is critical for initiation and propagation of action potentials. Milliseconds after the pore opens, sodium influx is terminated by inactivation processes mediated by regulatory proteins including calmodulin (CaM). Both calcium-free (apo) CaM and calcium-saturated CaM bind tightly to an IQ motif in the C-terminal tail of the alpha-subunit. Our thermodynamic studies and solution structure (2KXW) of a C-domain fragment of apo (13)C,(15)N- CaM (CaMC) bound to an unlabeled peptide with the sequence of rat NaV1.2 IQ motif showed that apo CaMC (a) was necessary and sufficient for binding, and (b) bound more favorably than calcium-saturated CaMC. However, we could not monitor the NaV1.2 residues directly, and no structure of full-length CaM (including the N-domain of CaM (CaMN)) was determined. To distinguish contributions of CaMN and CaMC, we used solution NMR spectroscopy to assign the backbone resonances of a complex containing a (13)C,(15)N-labeled peptide with the sequence of human NaV1.2 IQ motif (NaV1.2IQp) bound to apo (13)C,(15)N-CaM or apo (13)C,(15)N-CaMC. Comparing the assignments of apo CaM in complex with NaV1.2IQp to those of free apo CaM showed that residues within CaMC were significantly perturbed, while residues within CaMN were essentially unchanged. The chemical shifts of residues in NaV1.2IQp and in the C-domain of CaM were nearly identical regardless of whether CaMN was covalently linked to CaMC. This suggests that CaMN does not influence apo CaM binding to NaV1.2IQp. Backbone resonance assignments of complexes of human voltage-dependent sodium channel NaV1.2 IQ motif peptide bound to apo calmodulin and to the C-domain fragment of apo calmodulin.,Mahling R, Kilpatrick AM, Shea MA Biomol NMR Assign. 2017 Oct;11(2):297-303. doi: 10.1007/s12104-017-9767-2. Epub, 2017 Aug 19. PMID:28823028[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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