常见的泛素化蛋白修饰.ppt

小结 Wechman et al., Nat. Rev. Mol. Cell Biol., 6,599-609 (2005) 59 课外作业题 简述泛素化的主要生物化学特点，并说明它在细胞活动中的作用。 简述蛋白酶体的组成及其与其它蛋白酶的主要差别。 简单介绍类泛素蛋白的种类及其主要功能。 60 The Biochemical Roles of Protein Degradation in a Cell 1. 溶酶体 (Lysosomes) Non-selective Hydrolyze proteins from autophagy Digest proteins from endocytosis Membrane proteins Extracellular proteins 2. 泛素-蛋白酶体通路 Selective and (Ubiquitin-Proteasome Pathway) ATP-Dependent Regulate biochemical reactions Discard unnecessary proteins Degrade damaged or misfolded proteins Present internalized antigens in immunological responses 29 ? ? ? ? 20S 催化颗粒 19S 调节颗粒 19S 10 nm 电镜下的26S蛋白酶体(Proteasome) Yifan Cheng, Xiao-Bo Qiu et al., unpublished data 30 26S 蛋白酶体的亚基组成 31 32 免疫蛋白酶体(Immunoproteasome)负责抗原提呈(Antigen Presentation) 免疫蛋白酶体的催化颗粒(20S) 有三个特殊亚单位LMP2、LMP7 和MECL-1。其调节颗粒为PA28（11S）。 20S颗粒 33 MHC class I antigen presentation pathway T cell Peptide MHC class I Protein antigen Proteasome +/- Ubiquitin Peptides (2-24 a.a.) TAP (8-16 a.a.) Endoplasmic Reticulum CD8+ Golgi 8-10 a.a. Amino acids ERAP1 34 35 The proteasome inhibitor, Velcade (Botezomib/PS-341), has been approved by FDA to treat multiple myeloma and mantle cell lymphoma . 36 中药雷公藤中的抗癌活性成分—雷公藤红素Celastrol是一种蛋白酶体抑制剂，它能通过控制癌细胞的蛋白酶体活性进而诱发癌细胞凋亡。 Yang, H. et al., Cancer Res. (2006) 37 1、 蛋白酶体亚单位hRpn13能激活存在于蛋白酶  体的去泛素化酶UCH37。2、 c-Abl通过引起蛋白酶体磷酸化而抑制其活性。 蛋白酶体的调控 38 hRpn13能激活去泛素化酶UCH37 control +hRpn13 S5a +hRpn13+Ub-H Qiu, X.B. * et al., EMBO J. （2006） 25:5742-5753. 39 其它研究表明Rpn13可作为泛素受体而结合于泛素链的近端 Husnjak et al. Nature 453:481, 2008 Schrener et al. Nature 453:548, 2008 41 c-Abl通过引起蛋白酶体磷酸化而抑制其活性 Liu, X., Huang, W., Li., C., Li, P., Yuan, J., Li, X., Qiu, X.B., Ma, Q., and Cao, C.(2006). Molecular Cell. 22, 317-327. 42 The 26S proteasome is a multisubunit complex, consisting of the 20S catalytic particle and the 19S regulatory particle, and selectively degrades ub