Center for Integrated Protein Science at the Department of Chemistry, Technical University of Munich, Lichtenbergstr. 4, 85748, Garching, Germany.
SciLifeLab, Department of Oncology-Pathology, Karolinska Institutet, Box 1031, 171 21 Solna, Stockholm, Sweden.
Nat Commun. 2019 Feb 8;10(1):672. doi: 10.1038/s41467-019-08632-0.
A fundamental step in membrane protein biogenesis is their integration into the lipid bilayer with a defined orientation of each transmembrane segment. Despite this, it remains unclear how cells detect and handle failures in this process. Here we show that single point mutations in the membrane protein connexin 32 (Cx32), which cause Charcot-Marie-Tooth disease, can cause failures in membrane integration. This leads to Cx32 transport defects and rapid degradation. Our data show that multiple chaperones detect and remedy this aberrant behavior: the ER-membrane complex (EMC) aids in membrane integration of low-hydrophobicity transmembrane segments. If they fail to integrate, these are recognized by the ER-lumenal chaperone BiP. Ultimately, the E3 ligase gp78 ubiquitinates Cx32 proteins, targeting them for degradation. Thus, cells use a coordinated system of chaperones for the complex task of membrane protein biogenesis, which can be compromised by single point mutations, causing human disease.
膜蛋白生物发生的一个基本步骤是将其整合到具有每个跨膜片段的特定取向的脂质双层中。尽管如此，细胞如何检测和处理该过程中的故障仍不清楚。在这里，我们表明，导致遗传性神经病 Charcot-Marie-Tooth 病的连接蛋白 32（Cx32）中的单点突变可导致膜整合失败。这导致 Cx32 运输缺陷和快速降解。我们的数据表明，多种伴侣蛋白可以检测和纠正这种异常行为：内质网-膜复合物（EMC）有助于低疏水性跨膜片段的膜整合。如果它们未能整合，则内质网腔伴侣蛋白 BiP 将识别它们。最终，E3 连接酶 gp78 泛素化 Cx32 蛋白，将其靶向降解。因此，细胞使用伴侣蛋白的协调系统来完成膜蛋白生物发生这一复杂任务，但单个点突变会破坏该系统，导致人类疾病。
