Ravid Tommer, Hochstrasser Mark
Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520, USA.
Nat Cell Biol. 2007 Apr;9(4):422-7. doi: 10.1038/ncb1558. Epub 2007 Feb 21.
Cells have quality-control mechanisms to recognize non-native protein structures and either help the proteins fold or promote their degradation. Ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s) work together to assemble polyubiquitin chains on misfolded or misassembled proteins, which are then degraded by the proteasome. Here, we find that Ubc7, a yeast E2, can itself undergo degradation when its levels exceed that of its binding partner Cue1, a transmembrane protein that tethers Ubc7 to the endoplasmic reticulum. Unassembled, and thus mislocalized, Ubc7 is targeted to the proteasome by Ufd4, a homologous to E6-AP C-terminus (HECT)-class E3. Ubc7 is autoubiquitinated by a novel mechanism wherein the catalytic cysteine, instead of a lysine residue, provides the polyubiquitin chain acceptor site, and this cysteine-linked chain functions as a degradation signal. The polyubiquitin chain can also be transferred to a lysine side chain, suggesting a mechanism for polyubiquitin chain assembly that precedes substrate modification.
细胞具有质量控制机制，以识别非天然蛋白质结构，并帮助蛋白质折叠或促进其降解。泛素结合酶（E2s）和泛素连接酶（E3s）共同作用，在错误折叠或组装错误的蛋白质上组装多聚泛素链，然后这些蛋白质被蛋白酶体降解。在这里，我们发现酵母E2 Ubc7当其水平超过其结合伴侣Cue1（一种将Ubc7 tether到内质网的跨膜蛋白）时，自身会发生降解。未组装从而定位错误的Ubc7被Ufd4靶向蛋白酶体，Ufd4是一种与E6-AP C末端（HECT）类E3同源的蛋白。Ubc7通过一种新机制进行自身泛素化，其中催化半胱氨酸而非赖氨酸残基提供多聚泛素链接受位点，并且这种半胱氨酸连接的链作为降解信号起作用。多聚泛素链也可以转移到赖氨酸侧链，这表明了一种在底物修饰之前的多聚泛素链组装机制。
