6MC9
Crystal Structure of Human Nav1.4 C-Terminal (1599-1754) domain in complex with calcium-bound calmodulin
Summary for 6MC9
| Entry DOI | 10.2210/pdb6mc9/pdb |
| Descriptor | Sodium channel protein type 4 subunit alpha, Calmodulin-1, CALCIUM ION (3 entities in total) |
| Functional Keywords | scn4a, voltage gated sodium channel, calmodulin, calmodulin-binding protein, protein binding |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 36224.80 |
| Authors | Yoder, J.B.,Gabelli, S.B.,Amzel, L.M. (deposition date: 2018-08-30, release date: 2019-04-10, Last modification date: 2023-10-11) |
| Primary citation | Yoder, J.B.,Ben-Johny, M.,Farinelli, F.,Srinivasan, L.,Shoemaker, S.R.,Tomaselli, G.F.,Gabelli, S.B.,Amzel, L.M. Ca2+-dependent regulation of sodium channels NaV1.4 and NaV1.5 is controlled by the post-IQ motif. Nat Commun, 10:1514-1514, 2019 Cited by PubMed Abstract: Skeletal muscle voltage-gated Na channel (Na1.4) activity is subject to calmodulin (CaM) mediated Ca-dependent inactivation; no such inactivation is observed in the cardiac Na channel (Na1.5). Taken together, the crystal structures of the Na1.4 C-terminal domain relevant complexes and thermodynamic binding data presented here provide a rationale for this isoform difference. A Ca-dependent CaM N-lobe binding site previously identified in Na1.5 is not present in Na1.4 allowing the N-lobe to signal other regions of the Na1.4 channel. Consistent with this mechanism, removing this binding site in Na1.5 unveils robust Ca-dependent inactivation in the previously insensitive isoform. These findings suggest that Ca-dependent inactivation is effected by CaM's N-lobe binding outside the Na C-terminal while CaM's C-lobe remains bound to the Na C-terminal. As the N-lobe binding motif of Na1.5 is a mutational hotspot for inherited arrhythmias, the contributions of mutation-induced changes in CDI to arrhythmia generation is an intriguing possibility. PubMed: 30944319DOI: 10.1038/s41467-019-09570-7 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.3 Å) |
Structure validation
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