Eukaryotic proteasomes cannot digest polyglutamine sequences and release them during degradation of polyglutamine-containing proteins
Eukaryotic proteasomes cannot digest polyglutamine sequences and release them during degradation of polyglutamine-containing proteins
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DOI：
10.1016/s1097-2765(04)00151-0
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发表时间：
2004-04-09
期刊：
影响因子：
16
通讯作者：
Goldberg, AL
中科院分区：
文献类型：
--
作者：
Venkatraman, P;Wetzel, R;Goldberg, AL
长谷氨酰胺序列(PolyQ)存在于许多细胞蛋白质中，一些神经退行性疾病是由这些序列的扩展引起的。含多聚Q的蛋白质被蛋白酶体降解，蛋白酶体的三个活性部位在疏水残基、碱性残基或酸性残基之后倾向于切割。我们测试了这些粒子是否能消化多聚Q链。真核细胞中的26S和20S蛋白酶体不能在多肽的9-29Q残基范围内切割。当消化肌红蛋白Q(35)融合蛋白时，蛋白酶体省去了多聚Q序列。相比之下，古生菌蛋白酶体，其14个活性位点不太特异，迅速消化这种多Q重复。因此，当降解多聚Q蛋白时，真核蛋白酶体必须释放易于聚集的含有多Q的片段，以便被未知的多肽酶进一步水解。在多Q疾病中，这样的多Q序列(38-300Q)超过了正常蛋白酶体产物的长度(2-25个残基)。这些无法降解的长序列偶尔无法退出可能会干扰蛋白酶体的功能，并有助于解释为什么较长的多聚Q扩增促进疾病的早期发病。
Long glutamine sequences (polyQ) occur in many cell proteins, and several neurodegenerative diseases result from expansion of these sequences. PolyQ-containing proteins are degraded by proteasomes, whose three active sites prefer to cleave after hydrophobic, basic, or acidic residues. We tested whether these particles can digest a polyQ chain. Eukaryotic 26S and 20S proteasomes failed to cut within stretches of 9-29Q residues in peptides. While digesting a myoglobin Q(35) fusion protein, the proteasomes spared the polyQ sequence. In contrast, archaeal proteasomes, whose 14 active sites are less specific, rapidly digested such polyQ repeats. Therefore, when degrading polyQ proteins, eukaryotic proteasomes must release aggregation-prone polyQ-containing fragments for further hydrolysis by unidentified peptidases. In polyQ diseases, such polyQ sequences (38-300Qs) exceed the lengths of normal proteasome products (2-25 residues). Occasional failure of these long undegradable sequences to exit may interfere with proteasome function and help explain why longer polyQ expansions promote early disease onset.