title: Ca(V)1.2 I-II linker structure and Timothy syndrome.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute of Structural Biology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Lior
authors.initials: L
authors.lastname: Almagor
authors.forename: Orna
authors.initials: O
authors.lastname: Chomsky-Hecht
authors.forename: Adva
authors.initials: A
authors.lastname: Ben-Mocha
authors.forename: Doran
authors.initials: D
authors.lastname: Hendin-Barak
authors.forename: Nathan
authors.initials: N
authors.lastname: Dascal
authors.forename: Joel A
authors.initials: JA
authors.lastname: Hirsch
mesh_terms: D000818:Animals; D001321:Autistic Disorder; D020746:Calcium Channels, L-Type / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D013576:Syndactyly / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D014981:Xenopus
chemical_list: D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C)