Proteasome active sites allosterically regulate each other, suggesting a cyclical bite-chew mechanism for protein breakdown
Proteasome active sites allosterically regulate each other, suggesting a cyclical bite-chew mechanism for protein breakdown
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DOI：
10.1016/s1097-2765(00)80341-x
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发表时间：
1999-09-01
期刊：
影响因子：
16
通讯作者：
Goldberg, AL
中科院分区：
文献类型：
--
作者：
Kisselev, AF;Akopian, TN;Goldberg, AL
在真核生物中，20 S蛋白酶体含有两个胰凝乳蛋白酶样，两个胰蛋白酶样，和两个活性位点，这里显示具有半胱天冬酶样特异性。我们报告说，某些网站变构调节对方的活动。胰凝乳蛋白酶样位点的底物显著地刺激半胱天冬酶样活性，并且还激活其它胰凝乳蛋白酶样位点。此外，半胱天冬酶样位点的底物变构抑制胰凝乳蛋白酶样活性（蛋白质分解的限速活性），从而可以减少26S蛋白酶体对蛋白质的降解。这些变构效应表明蛋白质降解的有序循环机制。我们建议，由于胰凝乳蛋白酶样网站最初切割（“咬”）的多肽，从而刺激半胱天冬酶样网站。它们的激活加速了片段的进一步切割（“咀嚼”），而胰凝乳蛋白酶样活性被暂时抑制。当进一步的半胱天冬酶样裂解是不可能的，胰凝乳蛋白酶的网站被重新激活和循环重复。
In eukaryotes, the 20S proteasome contains two chymotrypsin-like, two trypsin-like, and two active sites shown here to have caspase-like specificity. We report that certain sites allosterically regulate each other's activities. Substrates of a chymotrypsin-like site stimulate dramatically the caspase-like activity and also activate the other chymotrypsin-like site. Moreover, substrates of the caspase-like sites inhibit allosterically the chymotrypsin-like activity (the rate-limiting one in protein breakdown) and thus can reduce the degradation of proteins by 26S proteasomes. These allosteric effects suggest an ordered, cyclical mechanism for protein degradation. We propose that due chymotrypsin-like site initially cleaves ("bites") the polypeptide, thereby stimulating the caspase-like sites. Their activation accelerates further cleavage ("chewing") of the fragments, while the chymotrypsin-like activity is temporarily inhibited. When further caspase-like cleavages are impossible, the chymotryptic site is reactivated and the cycle repeated.