Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland.
Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland.
Sci Adv. 2023 Sep;9(35):eadh4890. doi: 10.1126/sciadv.adh4890. Epub 2023 Aug 30.
In myelinating Schwann cells, connection between myelin layers is mediated by gap junction channels (GJCs) formed by docked connexin 32 (Cx32) hemichannels (HCs). Mutations in Cx32 cause the X-linked Charcot-Marie-Tooth disease (CMT1X), a degenerative neuropathy without a cure. A molecular link between Cx32 dysfunction and CMT1X pathogenesis is still missing. Here, we describe the high-resolution cryo-electron cryo-myography (cryo-EM) structures of the Cx32 GJC and HC, along with two CMT1X-linked mutants, W3S and R22G. While the structures of wild-type and mutant GJCs are virtually identical, the HCs show a major difference: In the W3S and R22G mutant HCs, the amino-terminal gating helix partially occludes the pore, consistent with a diminished HC activity. Our results suggest that HC dysfunction may be involved in the pathogenesis of CMT1X.
在髓鞘形成施万细胞中,髓鞘层之间的连接是由连接蛋白 32 (Cx32) 连接的间隙连接通道 (GJCs) 介导的。Cx32 突变导致 X 连锁遗传性运动感觉神经病(CMT1X),这是一种无法治愈的退行性神经病。Cx32 功能障碍与 CMT1X 发病机制之间的分子联系仍然缺失。在这里,我们描述了 Cx32 GJC 和 HC 的高分辨率冷冻电镜 cryo-myography (cryo-EM) 结构,以及两种 CMT1X 相关突变体 W3S 和 R22G。尽管野生型和突变型 GJCs 的结构几乎相同,但 HC 显示出一个主要差异:在 W3S 和 R22G 突变体 HC 中,氨基末端门控螺旋部分阻塞了孔道,与 HC 活性降低一致。我们的结果表明,HC 功能障碍可能与 CMT1X 的发病机制有关。