Format

Send to

Choose Destination
Channels (Austin). 2012 Nov-Dec;6(6):468-72. doi: 10.4161/chan.22078. Epub 2012 Sep 18.

Ca(V)1.2 I-II linker structure and Timothy syndrome.

Author information

1
Department of Biochemistry and Molecular Biology, Institute of Structural Biology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.

Abstract

Ca(V) channels are multi-subunit protein complexes that enable inward cellular Ca(2+) currents in response to membrane depolarization. We recently described structure-function studies of the intracellular α1 subunit domain I-II linker, directly downstream of domain IS6. The results show the extent of the linker's helical structure to be subfamily dependent, as dictated by highly conserved primary sequence differences. Moreover, the difference in structure confers different biophysical properties, particularly the extent and kinetics of voltage and calcium-dependent inactivation. Timothy syndrome is a human genetic disorder due to mutations in the Ca(V)1.2 gene. Here, we explored whether perturbation of the I-II linker helical structure might provide a mechanistic explanation for a Timothy syndrome mutant's (human Ca(V)1.2 G406R equivalent) biophysical effects on inactivation and activation. The results are equivocal, suggesting that a full mechanistic explanation for this Timothy syndrome mutation requires further investigation.

PMID:
22990809
PMCID:
PMC3536733
DOI:
10.4161/chan.22078
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Taylor & Francis Icon for PubMed Central
Loading ...
Support Center