METHOTREXATE INHIBITS PROTEOLYSIS OF DIHYDROFOLATE-REDUCTASE BY THE N-END RULE PATHWAY
METHOTREXATE INHIBITS PROTEOLYSIS OF DIHYDROFOLATE-REDUCTASE BY THE N-END RULE PATHWAY
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DOI：
10.1074/jbc.270.14.8172
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发表时间：
1995-04-07
影响因子：
4.8
通讯作者：
VARSHAVSKY, A
中科院分区：
文献类型：
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作者：
JOHNSTON, JA;JOHNSON, ES;VARSHAVSKY, A
N-末端规则将蛋白质的体内半衰期与其N-末端残基的身份联系起来。在真核生物中，N-末端规则途径是一种泛素依赖的、基于蛋白酶体的系统，其靶向并促降解具有某些N-末端残基的蛋白质。Arg-DHFR是一种修饰的二氢叶酸还原酶，带有N-末端精氨酸（N-末端规则中的不稳定残基），在补充ATP的网织红细胞提取物中寿命较短。甲氨蝶呤是叶酸类似物和DHFR的高亲和力配体，它通过N端规则途径抑制Arg-DHFR的降解，但不抑制其泛素化。其他N-末端规则底物的降解不受甲氨蝶呤的影响。我们讨论了这些结果的影响，蛋白酶体介导的蛋白质降解的机制。
The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. In eukaryotes, the N-end rule pathway is a ubiquitin-dependent, proteasome-based system that targets and processively degrades proteins bearing certain N-terminal residues. Arg-DHFR, a modified dihydrofolate reductase bearing an N-terminal arginine (destabilizing residue in the N-end rule), is short lived in ATP-supplemented reticulocyte extract. It is shown here that methotrexate, which is a folic acid analog and high affinity ligand of DHFR, inhibits the degradation but not ubiquitination of Arg-DHFR by the N-end rule pathway. The degradation of other N-end rule substrates is not affected by methotrexate. We discuss implications of these results for the mechanism of proteasome-mediated protein degradation.