CIC-7 is a slowly voltage-gated 2CI-/1H+-exchanger and requires Ostm1 for transport activity
CIC-7 is a slowly voltage-gated 2CI-/1H+-exchanger and requires Ostm1 for transport activity
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DOI：
10.1038/emboj.2011.137
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发表时间：
2011-06-01
期刊：
影响因子：
11.4
通讯作者：
Stauber, Tobias
中科院分区：
文献类型：
--
作者：
Leisle, Lilia;Ludwig, Carmen F.;Stauber, Tobias
CIC-7/Ostm1 离子转运蛋白的突变会导致骨硬化症和溶酶体贮积症。迄今为止，其溶酶体定位还无法进行详细的功能表征。使用到达质膜的突变 CIC-7，我们现在表明 Ostm1 β 亚基的氨基末端和跨膜跨度都是 CIC-7 CI-/H+ 交换所必需的，而 Ostm1 跨膜结构域足以满足其 CIC-7 依赖的向溶酶体的运输。由于离子交换门控缓慢，CIC-7/Ostm1 电流强烈向外整流，其本身表现出本质上几乎线性的电压依赖性。尾电流的反转电位揭示了2CI(-)/1H(+)-交换化学计量。几种致病的 CLCN7 突变加速了门控。此类突变聚集在第二个胞质胱硫醚-β-合酶结构域和跨膜片段的潜在接触位点。我们的工作表明，门控是所有内体/溶酶体 CLC 整流的基础，并将电压门控的概念从通道扩展到离子交换器。 EMBO 杂志 (2011) 30, 2140-2152。 doi：10.1038/emboj.2011.137； 2011 年 4 月 28 日在线发布
Mutations in the CIC-7/Ostm1 ion transporter lead to osteopetrosis and lysosomal storage disease. Its lysosomal localization hitherto precluded detailed functional characterization. Using a mutated CIC-7 that reaches the plasma membrane, we now show that both the aminoterminus and transmembrane span of the Ostm1 beta-subunit are required for CIC-7 CI-/H+-exchange, whereas the Ostm1 transmembrane domain suffices for its CIC-7-dependent trafficking to lysosomes. CIC-7/Ostm1 currents were strongly outwardly rectifying owing to slow gating of ion exchange, which itself displays an intrinsically almost linear voltage dependence. Reversal potentials of tail currents revealed a 2CI(-)/1H(+)-exchange stoichiometry. Several disease-causing CLCN7 mutations accelerated gating. Such mutations cluster to the second cytosolic cystathionine-beta-synthase domain and potential contact sites at the transmembrane segment. Our work suggests that gating underlies the rectification of all endosomal/lysosomal CLCs and extends the concept of voltage gating beyond channels to ion exchangers. The EMBO Journal (2011) 30, 2140-2152. doi:10.1038/emboj.2011.137; Published online 28 April 2011