Na1.2 EFL Domain Allosterically Enhances Ca Binding to Sites I and II of WT and Pathogenic Calmodulin Mutants Bound to the Channel CTD

Overview

Journal Structure

Publisher Cell Press

Specialties Biochemistry
Biotechnology
Cell Biology
Molecular Biology

Date 2021 Mar 26

PMID 33770503

Citations 4

Authors

Ryan Mahling

Liam Hovey

Holly M Isbell

Dagan C Marx

Mark S Miller

Adina M Kilpatrick

Lisa D Weaver

Jesse B Yoder

Elaine H Kim

Corinne N J Andresen

Shuxiang Li

Madeline A Shea

Affiliations

Soon will be listed here.

Abstract

Neuronal voltage-gated sodium channel Na1.2 C-terminal domain (CTD) binds calmodulin (CaM) constitutively at its IQ motif. A solution structure (6BUT) and other NMR evidence showed that the CaM N domain (CaM) is structurally independent of the C-domain (CaM) whether CaM is bound to the Na1.2 (1,901-1,927) or Na1.2 (1,777-1,937) with or without calcium. However, in the CaM + Na1.2 complex, the Ca affinity of CaM was more favorable than in free CaM, while Ca affinity for CaM was weaker than in the CaM + Na1.2 complex. The CTD EF-like (EFL) domain allosterically widened the energetic gap between CaM domains. Cardiomyopathy-associated CaM mutants (N53I(N54I), D95V(D96V), A102V(A103V), E104A(E105A), D129G(D130G), and F141L(F142L)) all bound the Na1.2 IQ motif favorably under resting (apo) conditions and bound calcium normally at CaM sites. However, only N53I and A102V bound calcium at CaM sites at [Ca] < 100 μM. Thus, they are expected to respond like wild-type CaM to Ca spikes in excitable cells.

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