The folding and targeting of hydrophobic transmembrane domains poses a major challenge to the cell. Several membrane proteins have been shown to gain some degree of secondary structure within the ribosome tunnel and to retain this conformation throughout maturation. However, there is little information on one of the largest classes of eukaryotic membrane proteins; the G protein-coupled receptors (GPCRs). In this study we show that the signal anchor domain of GPR35 remains in an extended conformation whilst exiting the ribosome tunnel, the polypeptide chain then forms interactions with components of the SRP targeting pathway, and the Sec61 translocon, resulting in a compacted conformation prior to integration into the ER membrane. We conclude that transmembrane structure is most likely adopted after the domain leaves the ribosome tunnel and that the interaction of the signal anchor with SRP is dependent on the native levels of hydrophobicity within the first transmembrane domain. Therefore, we propose a mechanism by which the first transmembrane domains of multi-spanning membrane proteins adopt compacted structures following SRP targeting but before insertion into the ER membrane.

中文翻译：

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疏水性而非二级结构对于依赖SRP的GPR35靶向ER膜至关重要。

疏水跨膜结构域的折叠和靶向对细胞构成了重大挑战。已经显示出几种膜蛋白在核糖体通道内获得一定程度的二级结构，并在整个成熟过程中保持这种构象。然而，关于最大种类的真核膜蛋白之一的信息很少。G蛋白偶联受体（GPCR）。在这项研究中，我们显示GPR35的信号锚结构域在离开核糖体隧道时仍保持扩展的构象，然后多肽链与SRP靶向途径的成分和Sec61 translocon形成相互作用，从而导致整合前的紧密构象进入ER膜。我们得出的结论是，在结构域离开核糖体通道后最可能采用跨膜结构，并且信号锚与SRP的相互作用取决于第一个跨膜结构域中的天然疏水性水平。因此，我们提出了一种机制，通过该机制，跨跨膜蛋白的第一个跨膜结构域在靶向SRP之后但插入ER膜之前采用紧密结构。