Rezvani K, Mee M, Dawson S, McIlhinney J, Fujita J, Mayer R J
Laboratory of Intracellular Proteolysis, School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, U.K.
Biochem Soc Trans. 2003 Apr;31(2):470-3. doi: 10.1042/bst0310470.
The six regulatory non-redundant ATPases in the base of the 19 S regulator of the 26 S proteasome belong to the AAA superfamily of ATPases. Yeast two-hybrid genetic screens, biochemical analyses and cell biological studies have identified and characterized new interactors of the human S6 (rpt3) and S8 (rpt6) ATPases of the 19 S regulator of the 26 S proteasome. The S6 ATPase interacts with gankyrin. This protein is found in purified human 26 S proteasomes and in a smaller complex(es) containing CDK4 and free S6 ATPase. Gankyrin overexpression causes the phosphorylation of the retinoblastoma protein (pRb) and the release of E2F transcription factor to trigger the expression of DNA synthesis genes. Gankyrin is oncogenic in nude mice and is overexpressed in hepatocellular carcinoma cells (HCCs). The S8 ATPase interacts with members of the large Homer-3 protein family. There are three Homer genes; the Homer 1 and 2 gene products control trafficking and calcium-store-related functions of metabotropic glutamate receptors (e.g. mGluR1alpha). Homer-3A11 by binding to the S8 ATPase brings mGluR1alpha to the 26 S proteasome for degradation. The degradation of mGluR1alpha is blocked by proteasomal inhibitors and by overexpression of the N-terminus of Homer which binds to the receptor. The S8 ATPase and mGluR1alpha are co-localized in Purkinje dendrites in rat cerebellum. The data are discussed in terms of the regulation of the cell cycle and glutaminergic receptor functions by the 26 S proteasome.
26S蛋白酶体19S调节因子基部的六个调控性非冗余ATP酶属于ATP酶的AAA超家族。酵母双杂交遗传筛选、生化分析和细胞生物学研究已经鉴定并表征了26S蛋白酶体19S调节因子的人源S6（rpt3）和S8（rpt6）ATP酶的新相互作用分子。S6 ATP酶与甘菊环蛋白相互作用。在纯化的人26S蛋白酶体以及包含CDK4和游离S6 ATP酶的较小复合物中发现了这种蛋白质。甘菊环蛋白的过表达导致视网膜母细胞瘤蛋白（pRb）磷酸化并释放E2F转录因子，从而触发DNA合成基因的表达。甘菊环蛋白在裸鼠中具有致癌性，并且在肝癌细胞（HCC）中过表达。S8 ATP酶与大型Homer-3蛋白家族的成员相互作用。有三个Homer基因；Homer 1和2基因产物控制代谢型谷氨酸受体（例如mGluR1α）的转运和钙储存相关功能。Homer-3A11通过与S8 ATP酶结合将mGluR1α带到26S蛋白酶体进行降解。蛋白酶体抑制剂和与受体结合的Homer N端过表达可阻断mGluR1α的降解。S8 ATP酶和mGluR1α在大鼠小脑的浦肯野树突中共定位。本文根据26S蛋白酶体对细胞周期和谷氨酰胺能受体功能的调节对数据进行了讨论。
