Journal
EMBO JOURNAL
Volume 39, Issue 5, Pages -Publisher
WILEY
DOI: 10.15252/embj.2019102622
Keywords
calmodulin; gating charge; IQ motif structure; open probability; surface expression
Categories
Funding
- NIH [T32 GM113770, T32 GM099608, R01 HL098200, R01 HL121059, R01 EY012347, R01MH097887, R01 AG017502, R01 NS078792]
- American Heart Association (AHA) [AHA 14PRE19900021]
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The L-type Ca2+ channel Ca(V)1.2 governs gene expression, cardiac contraction, and neuronal activity. Binding of alpha-actinin to the IQ motif of Ca(V)1.2 supports its surface localization and postsynaptic targeting in neurons. We report a bi-functional mechanism that restricts Ca(V)1.2 activity to its target sites. We solved separate NMR structures of the IQ motif (residues 1,646-1,664) bound to alpha-actinin-1 and to apo-calmodulin (apoCaM). The Ca(V)1.2 K1647A and Y1649A mutations, which impair alpha-actinin-1 but not apoCaM binding, but not the F1658A and K1662E mutations, which impair apoCaM but not alpha-actinin-1 binding, decreased single-channel open probability, gating charge movement, and its coupling to channel opening. Thus, alpha-actinin recruits Ca(V)1.2 to defined surface regions and simultaneously boosts its open probability so that Ca(V)1.2 is mostly active when appropriately localized.
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