Mammalian odorant receptors are a diverse and rapidly evolving set of G protein-coupled receptors expressed in olfactory cilia membranes. Most odorant receptors show little to no cell surface expression in nonolfactory cells due to endoplasmic reticulum retention, which has slowed down biochemical studies. Here we provide evidence that structural instability and divergence from conserved residues of individual odorant receptors underlie intracellular retention using a combination of large-scale screening of odorant receptors cell surface expression in heterologous cells, point mutations, structural modeling, and machine learning techniques. We demonstrate the importance of conserved residues by synthesizing consensus odorant receptors that show high levels of cell surface expression similar to conventional G protein-coupled receptors. Furthermore, we associate in silico structural instability with poor cell surface expression using molecular dynamics simulations. We propose an enhanced evolutionary capacitance of olfactory sensory neurons that enable the functional expression of odorant receptors with cryptic mutations.

中文翻译：

---

结构不稳定性和与保守残基的分歧是哺乳动物气味受体细胞内滞留的基础。

哺乳动物气味受体是一组多样化且快速发展的 G 蛋白偶联受体，在嗅毛膜中表达。由于内质网滞留，大多数气味受体在非嗅觉细胞中几乎没有细胞表面表达，这减缓了生化研究。在这里，我们提供的证据表明，结构不稳定性和与个体气味受体保守残基的差异是细胞内滞留的基础，结合大规模筛选异源细胞中的气味受体细胞表面表达、点突变、结构建模和机器学习技术。我们通过合成一致的气味受体来证明保守残基的重要性，这些受体显示出类似于常规 G 蛋白偶联受体的高水平细胞表面表达。此外，我们使用分子动力学模拟将计算机结构不稳定性与细胞表面表达差相关联。我们提出了嗅觉感觉神经元的增强进化电容，使具有隐蔽突变的气味受体的功能表达成为可能。