Localization of a disease-associated mutation site in the three-dimensional structure of the cardiac muscle ryanodine receptor
Localization of a disease-associated mutation site in the three-dimensional structure of the cardiac muscle ryanodine receptor
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DOI：
10.1074/jbc.m505714200
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发表时间：
2005-11-11
影响因子：
4.8
通讯作者：
Wagenknecht, T
中科院分区：
文献类型：
--
作者：
Liu, Z;Wang, RW;Wagenknecht, T
心肌兰尼碱受体（RyR 2）在心脏中起钙释放通道的作用。RyR 2中多达40个突变与心脏性猝死的遗传形式有关。这些突变主要集中在多肽序列的三个区域：一个靠近N末端，一个在中心区域，第三个在C末端区域。中心区域包括11个突变，并且预测同一区域中的异亮氨酸-脯氨酸基序（位置2427和2428）有助于FKBP 12.6蛋白的结合。我们绘制了中心突变位点的三维结构的RyR 2的绿色荧光蛋白插入，冷冻电子显微镜，和单粒子图像处理。中心突变位点被映射到连接细胞质结构域5和6的密度“桥”，其被认为在通道门控期间经历构象变化。此外，该中心突变位点的位置并不接近先前通过冷冻电子显微镜绘制的FKBP12.6结合位点。
The cardiac muscle ryanodine receptor (RyR2) functions as a calcium release channel in the heart. Up to 40 mutations in RyR2 have been linked to genetic forms of sudden cardiac death. These mutations are largely clustered in three regions of the sequence of the polypeptide: one near the N terminus, one in the central region, and the third in the C-terminal region. The central region includes 11 mutations, and an isoleucine-proline motif ( positions 2427 and 2428) in the same region is predicted to contribute to the binding of FKBP12.6 protein. We have mapped the central mutation site in the three-dimensional structure of RyR2 by green fluorescent protein insertion, cryoelectron microscopy, and single-particle image processing. The central mutation site was mapped to a "bridge" of density that connects cytoplasmic domains 5 and 6, which have been suggested to undergo conformational changes during channel gating. Moreover, the location of this central mutation site is not close to that of the FKBP12.6-binding site mapped previously by cryoelectron microscopy.