Kv3.3 Channels Bind Hax-1 and Arp2/3 to Assemble a Stable Local Actin Network that Regulates Channel Gating.
Kv3.3 Channels Bind Hax-1 and Arp2/3 to Assemble a Stable Local Actin Network that Regulates Channel Gating.
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DOI：
10.1016/j.cell.2016.02.009
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发表时间：
2016-04-07
期刊：
影响因子：
64.5
通讯作者：
Kaczmarek LK
中科院分区：
文献类型：
--
作者：
Zhang Y;Zhang XF;Fleming MR;Amiri A;El-Hassar L;Surguchev AA;Hyland C;Jenkins DP;Desai R;Brown MR;Gazula VR;Waters MF;Large CH;Horvath TL;Navaratnam D;Vaccarino FM;Forscher P;Kaczmarek LK
Kv3.3 钾通道 (KCNC3) 突变会导致小脑神经变性并损害听觉处理。 Kv3.3 的细胞质 C 末端含有富含脯氨酸的结构域，该结构域保守于通过 Arp2/3 激活肌动蛋白成核的蛋白质中。我们发现 Kv3.3 将 Arp2/3 募集到质膜，从而形成相对稳定的皮质肌动蛋白丝网络，对细胞松弛素 D 具有抵抗力，细胞松弛素 D 抑制快速倒刺末端肌动蛋白组装。这些 Kv3.3 相关肌动蛋白结构需要防止质膜短暂去极化期间非常快速的 N 型通道失活。 Kv3.3 对肌动蛋白细胞骨架的影响是通过 Kv3.3 的细胞质 C 末端与 Hax-1 的结合介导的，Hax-1 是一种抗凋亡蛋白，通过 Arp2/3 调节肌动蛋白成核。富含脯氨酸的保守结构域内的人类 Kv3.3 突变会产生结合 Hax-1 的通道，但在将 Arp2/3 招募到质膜方面受到损害，导致干细胞衍生神经元中的生长锥肌动蛋白面纱缺陷。
Mutations in the Kv3.3 potassium channel (KCNC3) cause cerebellar neurodegeneration and impair auditory processing. The cytoplasmic C-terminus of Kv3.3 contains a proline-rich domain conserved in proteins that activate actin nucleation through Arp2/3. We found that Kv3.3 recruits Arp2/3 to the plasma membrane, resulting in formation of a relatively stable cortical actin filament network resistant to cytochalasin D which inhibits fast barbed end actin assembly. These Kv3.3-associated actin structures are required to prevent very rapid N-type channel inactivation during short depolarizations of the plasma membrane. The effects of Kv3.3 on the actin cytoskeleton are mediated by the binding of the cytoplasmic C-terminus of Kv3.3 to Hax-1, an anti-apoptotic protein that regulates actin nucleation through Arp2/3. A human Kv3.3 mutation within a conserved proline-rich domain produces channels that bind Hax-1 but are impaired in recruiting Arp2/3 to the plasma membrane, resulting in growth cones with deficient actin veils in stem cell-derived neurons.