Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Mol Cell. 2012 Nov 30;48(4):601-11. doi: 10.1016/j.molcel.2012.08.029. Epub 2012 Oct 4.
Poorly structured domains in proteins enhance their susceptibility to proteasomal degradation. To learn whether the presence of such a domain near either end of a protein determines its direction of entry into the proteasome, directional translocation was enforced on several proteasome substrates. Using archaeal PAN-20S complexes, mammalian 26S proteasomes, and cultured cells, we identified proteins that are degraded exclusively from either the C or N terminus and some showing no directional preference. This property results from interactions of the substrate's termini with the regulatory ATPase and could be predicted based on the calculated relative stabilities of the N and C termini. Surprisingly, the direction of entry into the proteasome affected markedly the spectrum of peptides released and consequently influenced the efficiency of MHC class I presentation. Thus, easily unfolded termini are translocated first, and the direction of translocation influences the peptides generated and presented to the immune system.
蛋白质中结构较差的结构域会增强其对蛋白酶体降解的敏感性。为了了解蛋白质两端附近是否存在这样的结构域是否决定了其进入蛋白酶体的方向，我们对几种蛋白酶体底物进行了定向易位。利用古细菌 PAN-20S 复合物、哺乳动物 26S 蛋白酶体和培养细胞，我们鉴定了仅从 C 端或 N 端降解的蛋白质，还有一些蛋白质没有表现出定向偏好。这种特性是由于底物末端与调节 ATP 酶的相互作用引起的，并且可以根据计算出的 N 和 C 末端的相对稳定性进行预测。令人惊讶的是，进入蛋白酶体的方向显著影响释放的肽谱，从而影响 MHC I 类呈递的效率。因此，容易展开的末端首先被易位，易位的方向影响生成并呈递给免疫系统的肽。
