| Autor: |
Turner, Matthew, Anderson, David E, Bartels, Peter, Nieves‐Cintron, Madeline, Coleman, Andrea M, Henderson, Peter B, Man, Kwun Nok Mimi, Tseng, Pang‐Yen, Yarov‐Yarovoy, Vladimir, Bers, Donald M, Navedo, Manuel F, Horne, Mary C, Ames, James B, Hell, Johannes W |
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| Zdroj: |
EMBO Journal; 3/2/2020, Vol. 39 Issue 5, p1-21, 21p, 2 Diagrams, 7 Charts, 5 Graphs |
| Abstrakt: |
The L‐type Ca2+ channel CaV1.2 governs gene expression, cardiac contraction, and neuronal activity. Binding of α‐actinin to the IQ motif of CaV1.2 supports its surface localization and postsynaptic targeting in neurons. We report a bi‐functional mechanism that restricts CaV1.2 activity to its target sites. We solved separate NMR structures of the IQ motif (residues 1,646–1,664) bound to α‐actinin‐1 and to apo‐calmodulin (apoCaM). The CaV1.2 K1647A and Y1649A mutations, which impair α‐actinin‐1 but not apoCaM binding, but not the F1658A and K1662E mutations, which impair apoCaM but not α‐actinin‐1 binding, decreased single‐channel open probability, gating charge movement, and its coupling to channel opening. Thus, α‐actinin recruits CaV1.2 to defined surface regions and simultaneously boosts its open probability so that CaV1.2 is mostly active when appropriately localized. Synopsis: Regulation of the L‐type voltage‐gated Ca2+ channel CaV1.2 by the EF hand proteins apo‐calmodulin (apoCaM) and α‐actinin remains debated. Here, structure‐function analyses report a dual role for α‐actinin‐1 in both instructing CaV1.2 cell surface localisation and increasing channel activity. NMR structures of ‐actinin‐1 and apoCaM EF3/4 hands bound to the CaV1.2 IQ motif identify distinct residues critical for binding.CaV1.2 IQ mutations impairing α‐actinin‐1 binding decrease channel open probability.CaV1.2 IQ mutations impairing apoCaM binding do not alter channel activity.α‐Actinin‐1 binding increases coupling of CaV1.2 gating charge movement to channel opening. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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