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The L-type Ca2+ channel CaV 1.2 governs gene expression, cardiac contraction, and neuronal activity. Binding of α-actinin to the IQ motif of CaV 1.2 supports its surface localization and postsynaptic targeting in neurons. We report a bi-functional mechanism that restricts CaV 1.2 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 CaV 1.2 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 CaV 1.2 to defined surface regions and simultaneously boosts its open probability so that CaV 1.2 is mostly active when appropriately localized. © 2020 The Authors.


Matthew Turner, David E Anderson, Peter Bartels, Madeline Nieves-Cintron, Andrea M Coleman, Peter B Henderson, Kwun Nok Mimi Man, Pang-Yen Tseng, Vladimir Yarov-Yarovoy, Donald M Bers, Manuel F Navedo, Mary C Horne, James B Ames, Johannes W Hell. α-Actinin-1 promotes activity of the L-type Ca2+ channel Cav 1.2. The EMBO journal. 2020 Mar 02;39(5):e102622

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PMID: 31985069

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