Structural and functional characterization of an achromatopsia-associated mutation in a phototransduction channel.
Structural and functional characterization of an achromatopsia-associated mutation in a phototransduction channel.
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DOI：
10.1038/s42003-022-03120-6
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发表时间：
2022-03-01
影响因子：
5.9
通讯作者：
Yang J
中科院分区：
文献类型：
--
作者：
Zheng X;Li H;Hu Z;Su D;Yang J
环核苷酸门控（CNG）通道中的许多错义突变导致色盲和视网膜色素变性，但潜在的致病机制往往不清楚。我们研究了R410 W的结构基础和分子/细胞效应，R410 W是人类CNGA 3中与色盲相关的假定功能丧失突变。携带类似突变R421 W的秀丽隐杆线虫TAX-4 CNG通道的冷冻电镜结构显示，大多数载脂蛋白通道是开放的。位于浇口环中的R421在关闭状态下与S4段相互作用。R421 W破坏了这种相互作用，破坏了关闭状态的稳定性，并稳定了打开状态。CNGA3_R410W/CNGB 3和TAX4_R421W通道在没有cGMP的情况下自发活性并诱导细胞死亡，表明自发CNG通道活性触发的视锥细胞变性是色盲的可能原因。我们的研究为CNG通道变构门控提供了新的线索，为重新评估报告的功能丧失CNG通道错义疾病突变提供了动力，并对视网膜病变的突变特异性治疗产生了影响。视锥光感受器CNG通道中的R410 W突变与色盲相关，并被认为是功能丧失变体，导致通道自发打开，如冷冻EM、电生理学和钙成像所揭示的，并且具有细胞毒性。这项研究呼吁多管齐下的评估/重新评估与CNG通道病相关的其他遗传性突变。
Numerous missense mutations in cyclic nucleotide-gated (CNG) channels cause achromatopsia and retinitis pigmentosa, but the underlying pathogenic mechanisms are often unclear. We investigated the structural basis and molecular/cellular effects of R410W, an achromatopsia-associated, presumed loss-of-function mutation in human CNGA3. Cryo-EM structures of the Caenorhabditis elegans TAX-4 CNG channel carrying the analogous mutation, R421W, show that most apo channels are open. R421, located in the gating ring, interacts with the S4 segment in the closed state. R421W disrupts this interaction, destabilizes the closed state, and stabilizes the open state. CNGA3_R410W/CNGB3 and TAX4_R421W channels are spontaneously active without cGMP and induce cell death, suggesting cone degeneration triggered by spontaneous CNG channel activity as a possible cause of achromatopsia. Our study sheds new light on CNG channel allosteric gating, provides an impetus for a reevaluation of reported loss-of-function CNG channel missense disease mutations, and has implications for mutation-specific treatment of retinopathy. The R410W mutation in the cone photoreceptor CNG channel, linked to achromatopsia and assumed to be a loss-of-function variant, causes the channel to open spontaneously as revealed by cryo-EM, electrophysiology and calcium imaging, and is cytotoxic. This study calls for a multipronged evaluation/reevaluation of other inherited mutations associated with CNG channelopathy.
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真核环核苷酸门控通道的结构。
影响因子：
64.8
作者：
Li M;Zhou X;Wang S;Michailidis I;Gong Y;Su D;Li H;Li X;Yang J
通讯作者：
Yang J
影响因子：
5.5
作者：
Dai, Gucan;Varnum, Michael D.
通讯作者：
Varnum, Michael D.
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
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
DOI：
10.1107/s2059798318006551
发表时间：
2018-06-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Poon BK;Read RJ;Sobolev OV;Terwilliger TC;Urzhumtsev A;Adams PD
通讯作者：
Adams PD