The structural mechanism of KCNH-channel regulation by the eag domain.
The structural mechanism of KCNH-channel regulation by the eag domain.
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作者：
KCNH电压依赖性钾通道（ether-á-go-go，EAG; EAG相关基因，ERG; EAG样通道，ELK）是细胞兴奋性的重要调节因子，在心脏长QT综合征2型（LQT 2）、癫痫、精神分裂症和癌症等疾病中发挥关键作用。KCNH通道的胞内结构域在结构上不同于其他电压门控通道。氨基末端区域含有eag结构域，其由Per-Arnt-Sim（PAS）结构域和PAS-帽结构域组成，而羧基末端区域含有通过C-接头结构域连接至孔的环核苷酸结合同源结构域（CNBHD）。许多致病突变定位于这些专门的细胞内结构域，这些结构域是KCNH通道独特的门控和调节的基础。已经表明eag结构域可以通过与S4-S5接头或CNBHD相互作用来调节通道。在这里，我们提出了一个2 μ m分辨率的晶体结构的小鼠EAG 1（mEAG 1）通道的eag域-CNBHD复合物。它显示了广泛的eag结构域和CNBHD之间的相互作用，表明eag结构域的调节机制主要涉及CNBHD。令人惊讶的是，该结构揭示了hERG中同源位置处的许多LQT 2突变和EAG通道中的癌症相关突变定位于eag结构域-CNBHD界面。此外，在接口处的突变对通道门控产生显著影响，证明了eag结构域-CNBHD相互作用的重要生理作用。我们的eag结构域的mEAG 1的CNBHD复合物的结构提供了独特的见解KCNH通道的生理和病理生理机制。
The KCNH voltage-dependent potassium channels (ether-á-go-go, EAG; EAG-related gene, ERG; EAG-like channels, ELK) are important regulators of cellular excitability and have key roles in diseases such as cardiac long QT syndrome type 2 (LQT2), epilepsy, schizophrenia and cancer. The intracellular domains of KCNH channels are structurally distinct from other voltage-gated channels. The amino-terminal region contains an eag domain, which is comprised of a Per-Arnt-Sim (PAS) domain and a PAS-cap domain, while the carboxy-terminal region contains a cyclic nucleotide-binding homology domain (CNBHD) which is connected to the pore through a C-linker domain. Many disease-causing mutations localize to these specialized intracellular domains, which underlie the unique gating and regulation of KCNH channels. It has been suggested that the eag domain may regulate the channel by interacting with either the S4-S5 linker or the CNBHD. Here we present a 2-Å resolution crystal structure of the eag domain-CNBHD complex of the mouse EAG1 (mEAG1) channel. It displays extensive interactions between the eag domain and the CNBHD, indicating that the regulatory mechanism of the eag domain involves primarily the CNBHD. Surprisingly, the structure reveals that a number of LQT2 mutations at homologous positions in hERG, and cancer-associated mutations in EAG channels, localize to the eag domain-CNBHD interface. Furthermore, mutations at the interface produced dramatic effects on channel gating demonstrating the important physiological role of the eag domain-CNBHD interaction. Our structure of the eag domain-CNBHD complex of mEAG1 provides unique insights into the physiological and pathophysiological mechanisms of KCNH channels.
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影响因子：
8.8
作者：
Bamford, S;Dawson, E;Forbes, S;Clements, J;Pettett, R;Dogan, A;Flanagan, A;Teague, J;Futreal, PA;Stratton, MR;Wooster, R
通讯作者：
Wooster, R
影响因子：
64.5
作者：
Cabral, JHM;Lee, A;Mackinnon, R
通讯作者：
Mackinnon, R
影响因子：
5.6
作者：
Marques-Carvalho, Maria J.;Sahoo, Nirakar;Morais-Cabral, Joao H.
通讯作者：
Morais-Cabral, Joao H.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
120.7
作者：
Napolitano, C;Priori, SG;Leonardi, S
通讯作者：
Leonardi, S