Atomic Mechanisms of Timothy Syndrome-Associated Mutations in Calcium Channel Cav1.2.

ABSTRACT: Timothy syndrome (TS) is a very rare multisystem disorder almost exclusively associated with mutations G402S and G406R in helix IS6 of Cav1.2. Recently, mutations R518C/H in helix IIS0 of the voltage sensing domain II (VSD-II) were described as a cause of cardiac-only TS. The three mutations are known to decelerate voltage-dependent inactivation (VDI). Here, we report a case of cardiac-only TS caused by mutation R518C. To explore possible impact of the three mutations on interdomain contacts, we modeled channel Cav1.2 using as templates Class Ia and Class II cryo-EM structures of presumably inactivated channel Cav1.1. In both models, R518 and several other residues in VSD-II donated H-bonds to the IS6-linked α1-interaction domain (AID). We further employed steered Monte Carlo energy minimi

SUBMITTER: Korkosh VS 

PROVIDER: S-EPMC6449482 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature