Anbanandam Asokan, Albarado Diana C, Tirziu Daniela C, Simons Michael, Veeraraghavan Sudha
Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Medical School, 6431 Fannin St., Houston, TX 77030, USA.
J Mol Biol. 2008 Dec 5;384(1):219-27. doi: 10.1016/j.jmb.2008.09.021. Epub 2008 Sep 16.
PR39, a naturally occurring and cell-permeable proline- and arginine-rich peptide, blocks the degradation of inhibitor of nuclear factor kappaB (IkappaBalpha), thereby attenuating inflammation. It is a noncompetitive and reversible inhibitor of 20S proteasome. To identify its basis of action, we used solution NMR spectroscopy and mutational analyses of the active fragment, PR11, which identified amino acids required for human 20S proteasome inhibiting activity. We then examined PR11-mediated changes in the expression of nuclear factor kappaB-dependent genes in situ. The results provide prerequisites for proteasome inhibition by proline- and arginine-rich peptides, providing a powerful new tool to investigate inflammatory processes. These findings offer new leads in developing drugs to treat heart diseases or stroke.
PR39是一种天然存在且可穿透细胞的富含脯氨酸和精氨酸的肽，它能阻止核因子κB抑制蛋白（IkappaBalpha）的降解，从而减轻炎症。它是20S蛋白酶体的非竞争性可逆抑制剂。为了确定其作用基础，我们使用溶液核磁共振光谱法以及对活性片段PR11进行突变分析，从而确定了人20S蛋白酶体抑制活性所需的氨基酸。然后我们原位检测了PR11介导的核因子κB依赖性基因表达的变化。这些结果为富含脯氨酸和精氨酸的肽抑制蛋白酶体提供了前提条件，为研究炎症过程提供了一个强大的新工具。这些发现为开发治疗心脏病或中风的药物提供了新线索。
