An intramembrane chaperone complex facilitates membrane protein biogenesis.
An intramembrane chaperone complex facilitates membrane protein biogenesis.
复制标题
DOI：
10.1038/s41586-020-2624-y
复制
发表时间：
2020-08
期刊：
影响因子：
64.8
通讯作者：
Hegde RS
中科院分区：
文献类型：
--
作者：
Chitwood PJ;Hegde RS
整合膜蛋白约占蛋白质编码基因的 25%。在真核生物中，绝大多数膜蛋白在内质网 (ER) 处插入、修饰和折叠。过去几十年的大量工作已经确定了膜蛋白如何靶向内质网以及单个跨膜结构域 (TMD) 如何插入脂质双层。相比之下，人们对具有多个 TMD 的蛋白质如何在膜内组装知之甚少。 TMD 的组装通常涉及极性或带电氨基酸，它们之间的相互作用稳定了最终的折叠构型。具有亲水性氨基酸的 TMD 很可能在共翻译膜蛋白生物发生过程中被陪伴，但内质网驻留的膜内陪伴分子的定义很差。在这里，我们鉴定了 PAT 复合物，这是 CCDC47 和 Asterix（两种广泛保守的 ER 驻留膜蛋白）的丰富的专性异二聚体。 PAT 复合物与脂质双层内含有未屏蔽亲水侧链的新生 TMD 结合，并伴随底物折叠而脱离。缺乏 PAT 复合物任一亚基的细胞表现出多种多跨膜蛋白的生物合成减少。因此，PAT 复合物是一种膜内伴侣，可在 TMD 组装过程中保护 TMD，从而最大限度地减少多跨膜蛋白的错误折叠并维持细胞蛋白稳态。
Integral membrane proteins represent approximately 25% of protein-coding genes. In eukaryotes, the vast majority of membrane proteins are inserted, modified, and folded at the endoplasmic reticulum (ER). Extensive work over the past several decades has determined how membrane proteins are targeted to the ER and how individual transmembrane domains (TMDs) are inserted into the lipid bilayer. By contrast, very little is known about how proteins with multiple TMDs are assembled within the membrane. Assembly of TMDs typically involves polar or charged amino acids whose interactions with each other stabilise the final folded configuration. TMDs with hydrophilic amino acids are likely to be chaperoned during co-translational membrane protein biogenesis, but ER-resident intramembrane chaperones are poorly defined. Here, we identify the PAT complex, an abundant obligate heterodimer of CCDC47 and Asterix, two widely conserved ER resident membrane proteins. The PAT complex engages nascent TMDs containing unshielded hydrophilic side chains within the lipid bilayer and disengages concomitant with substrate folding. Cells lacking either subunit of the PAT complex show reduced biogenesis of numerous multi-spanning membrane proteins. Thus, the PAT complex is an intramembrane chaperone that protects TMDs during their assembly to minimise misfolding of multi- spanning membrane proteins and maintain cellular protein homeostasis.
登录
查看更多内容
影响因子：
16.2
作者：
Gu, Shenyan;Matta, Jose A.;Bredt, David S.
通讯作者：
Bredt, David S.
影响因子：
9.8
作者：
Morimoto, Marie;Waller-Evans, Helen;Malicdan, May Christine V.
通讯作者：
Malicdan, May Christine V.
影响因子：
5.7
作者：
Harrington, Susan E.;Ben-Tal, Nir
通讯作者：
Ben-Tal, Nir
影响因子：
64.5
作者：
GORLICH, D;RAPOPORT, TA
通讯作者：
RAPOPORT, TA
影响因子：
3.3
作者：
Sato, K;Sato, M;Nakano, A
通讯作者：
Nakano, A