文章基本信息

标题：STAC proteins associate to the IQ domain of CaV1.2 and inhibit calcium-dependent inactivation
本地全文：下载
作者：Marta Campiglio ; Pierre Costé de Bagneaux ; Nadine J. Ortner 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2018
卷号：115
期号：6
页码：1376-1381
DOI：10.1073/pnas.1715997115
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The adaptor proteins STAC1, STAC2, and STAC3 represent a newly identified family of regulators of voltage-gated calcium channel (Ca_V) trafficking and function. The skeletal muscle isoform STAC3 is essential for excitation–contraction coupling and its mutation causes severe muscle disease. Recently, two distinct molecular domains in STAC3 were identified, necessary for its functional interaction with Ca_V1.1: the C1 domain, which recruits STAC proteins to the calcium channel complex in skeletal muscle triads, and the SH3-1 domain, involved in excitation–contraction coupling. These interaction sites are conserved in the three STAC proteins. However, the molecular domain in Ca_V1 channels interacting with the STAC C1 domain and the possible role of this interaction in neuronal Ca_V1 channels remained unknown. Using Ca_V1.2/2.1 chimeras expressed in dysgenic (Ca_V1.1^−/−) myotubes, we identified the amino acids 1,641–1,668 in the C terminus of Ca_V1.2 as necessary for association of STAC proteins. This sequence contains the IQ domain and alanine mutagenesis revealed that the amino acids important for STAC association overlap with those making contacts with the C-lobe of calcium-calmodulin (Ca/CaM) and mediating calcium-dependent inactivation of Ca_V1.2. Indeed, patch-clamp analysis demonstrated that coexpression of either one of the three STAC proteins with Ca_V1.2 opposed calcium-dependent inactivation, although to different degrees, and that substitution of the Ca_V1.2 IQ domain with that of Ca_V2.1, which does not interact with STAC, abolished this effect. These results suggest that STAC proteins associate with the Ca_V1.2 C terminus at the IQ domain and thus inhibit calcium-dependent feedback regulation of Ca_V1.2 currents.
关键词：STAC ; calcium-dependent inactivation ; voltage-gated calcium channels ; calmodulin