Department of Biochemistry, The Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa 31096, Israel.
Department of Biochemistry, The Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa 31096, Israel.
J Biol Chem. 2011 Sep 2;286(35):30274-30283. doi: 10.1074/jbc.M111.240309. Epub 2011 Jul 6.
The 26 S proteasome is the eukaryotic protease responsible for the degradation of most cellular proteins. As such it accommodates the ability to function under diverse conditions that the cell may encounter. This function is supported by various adaptors that modulate various aspects in protein degradation, these include regulation of substrate delivery, deubiquitination, unfolding, and 20 S gate dilation. Here we show a new functional complex between the P97 and the proteasome that is assembled in response to proteasomal impairment. This entails P97 binding to the 26 S proteasome via the 19 S particle thereby forming an additional hexameric ATPase ring to relieve repression. P97-bound proteasomes showed selective binding toward the Npl4-ufd1 P97 co-factors, indicating a unique cellular role for P97 binding to proteasomes. P97-bound proteasomes display enhanced activity, showing a relief in proteolysis impairment. Our findings place P97 directly in non-ERAD proteasomal functions and establish a new checkpoint in UPS impairment. The ability to modulate proteasome activity and properly respond to protein misfolding, is of great importance in cellular regulation.
26S 蛋白酶体是真核生物中负责降解大多数细胞内蛋白质的蛋白酶。因此，它能够适应细胞可能遇到的各种不同条件。这种功能由各种衔接蛋白支持，这些蛋白调节蛋白质降解的各个方面，包括调节底物的传递、去泛素化、展开和 20S 门的扩张。在这里，我们展示了一种新的 P97 和蛋白酶体之间的功能性复合物，该复合物是在蛋白酶体受损时组装的。这需要 P97 通过 19S 颗粒与 26S 蛋白酶体结合，从而形成一个额外的六聚体 ATP 酶环以解除抑制。与 P97 结合的蛋白酶体对 Npl4-ufd1 P97 共因子表现出选择性结合，表明 P97 与蛋白酶体的结合具有独特的细胞功能。与 P97 结合的蛋白酶体显示出增强的活性，显示出对蛋白水解损伤的缓解。我们的发现将 P97 直接置于非 ERAD 蛋白酶体功能中，并在 UPS 损伤中建立了一个新的检查点。调节蛋白酶体活性和正确应对蛋白质错误折叠的能力，对细胞调控非常重要。
