Ubiquitin Chain Trimming Recycles the Substrate Binding Sites of the 26 S Proteasome and Promotes Degradation of Lysine 48-linked Polyubiquitin Conjugates*
Ubiquitin Chain Trimming Recycles the Substrate Binding Sites of the 26 S Proteasome and Promotes Degradation of Lysine 48-linked Polyubiquitin Conjugates*
复制标题
泛素链修剪可回收 26 S 蛋白酶体的底物结合位点并促进赖氨酸 48 连接的多聚泛素缀合物的降解*
DOI：
10.1074/jbc.m111.260505
复制
发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Chang
中科院分区：
文献类型：
--
作者：
N. Zhang;A. Jacobson;A. MacFadden;Chang
26 S蛋白酶体具有两种不同的去泛素化活性。泛素（Ub）链切除活性从底物中去除整个polyUb链。Ub链修剪活性从远端逐渐切割polyUb链。Ub链切断活性介导降解偶联的去泛素化。Ub链修剪活性可以在降解中起支持或抑制作用，可能取决于底物的特征。Ub链修剪如何帮助降解尚不清楚。我们发现用Ub醛抑制26 S蛋白酶体的链修剪活性可显著抑制Ub 4（Lys-48）-UbcH 10的降解，并导致可保留在蛋白酶体上的游离Ub 4（由链切断产生）的积累。此外，不可修剪的Lys-48模拟物Ub 4有效地将UbcH 10靶向26 S蛋白酶体，但与常规Lys-48 Ub 4相比，它不能支持UbcH 10的有效降解。这些结果表明，polyUb链修剪促进蛋白酶体降解的Lys-48连接的底物。从机制上讲，我们建议Ub链修剪切割蛋白酶体结合的Lys-48连接的polyUb链，腾出26 S蛋白酶体的Ub结合位点，从而允许连续的底物加载。
The 26 S proteasome possesses two distinct deubiquitinating activities. The ubiquitin (Ub) chain amputation activity removes the entire polyUb chain from the substrates. The Ub chain trimming activity progressively cleaves a polyUb chain from the distal end. The Ub chain amputation activity mediates degradation-coupled deubiquitination. The Ub chain trimming activity can play a supportive or an inhibitory role in degradation, likely depending on features of the substrates. How Ub chain trimming assists degradation is not clear. We find that inhibition of the chain trimming activity of the 26 S proteasome with Ub aldehyde significantly inhibits degradation of Ub4 (Lys-48)-UbcH10 and causes accumulation of free Ub4 (generated from chain amputation) that can be retained on the proteasome. Also, a non-trimmable Lys-48-mimic Ub4 efficiently targets UbcH10 to the 26 S proteasome, but it cannot support efficient degradation of UbcH10 compared with regular Lys-48 Ub4. These results indicate that polyUb chain trimming promotes proteasomal degradation of Lys-48-linked substrates. Mechanistically, we propose that Ub chain trimming cleaves the proteasome-bound Lys-48-linked polyUb chains, which vacates the Ub binding sites of the 26 S proteasome, thus allowing continuous substrate loading.
登录
查看更多内容
影响因子：
2.9
作者：
Luming Yin;Bryan A. Krantz;N. Russell;Seema S. Deshpande;Keith D. Wilkinson
通讯作者：
Luming Yin;Bryan A. Krantz;N. Russell;Seema S. Deshpande;Keith D. Wilkinson
影响因子：
16
作者：
Leggett, DS;Hanna, J;Finley, D
通讯作者：
Finley, D
影响因子：
16
作者：
Tomko RJ Jr;Funakoshi M;Schneider K;Wang J;Hochstrasser M
通讯作者：
Hochstrasser M
影响因子：
16.6
作者：
Finley D
通讯作者：
Finley D
影响因子：
2.9
作者：
N. Russell;K. Wilkinson
通讯作者：
N. Russell;K. Wilkinson