Department of Physiology and Biophysics, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
EMBO J. 2010 Dec 1;29(23):3939-51. doi: 10.1038/emboj.2010.271. Epub 2010 Nov 2.
The mechanisms that couple translation and protein processing are poorly understood in higher eukaryotes. Although mammalian target of rapamycin (mTOR) complex 1 (mTORC1) controls translation initiation, the function of mTORC2 in protein synthesis remains to be defined. In this study, we find that mTORC2 can colocalize with actively translating ribosomes and can stably interact with rpL23a, a large ribosomal subunit protein present at the tunnel exit. Exclusively during translation of Akt, mTORC2 mediates phosphorylation of the nascent polypeptide at the turn motif (TM) site, Thr450, to avoid cotranslational Akt ubiquitination. Constitutive TM phosphorylation occurs because the TM site is accessible, whereas the hydrophobic motif (Ser473) site is concealed in the ribosomal tunnel. Thus, mTORC2 can function cotranslationally by phosphorylating residues in nascent chains that are critical to attain proper conformation. Our findings reveal that mTOR links protein production with quality control.
在高等真核生物中，将翻译与蛋白质加工偶联的机制还了解甚少。虽然雷帕霉素靶蛋白（mTOR）复合物 1（mTORC1）控制翻译起始，但 mTORC2 在蛋白质合成中的功能仍有待确定。在这项研究中，我们发现 mTORC2 可以与正在翻译的核糖体共定位，并可以与 rpL23a 稳定相互作用，rpL23a 是一种存在于隧道出口的大核糖体亚基蛋白。仅在 Akt 的翻译过程中，mTORC2 介导新生多肽在转弯模体（TM）位点 Thr450 处的磷酸化，以避免共翻译的 Akt 泛素化。组成性 TM 磷酸化发生是因为 TM 位点是可及的，而疏水性模体（Ser473）位点在核糖体隧道中被隐藏。因此，mTORC2 可以通过磷酸化对获得正确构象至关重要的新生链中的残基来发挥共翻译功能。我们的发现揭示了 mTOR 将蛋白质生产与质量控制联系起来。
