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用于丝氨酸蛋白酶抑制剂对木瓜蛋白酶进行交叉类别抑制的内肽酶2A的多个结构域

Multiple domains of endopin 2A for serpin cross-class inhibition of papain.

作者信息

Hwang Shin-Rong, Hook Vivian Y H

机构信息

Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093-0744, USA.

出版信息

Arch Biochem Biophys. 2007 May 15;461(2):219-24. doi: 10.1016/j.abb.2007.02.036. Epub 2007 Mar 21.

DOI:10.1016/j.abb.2007.02.036
PMID:17451636
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2745395/
Abstract

The serpin endopin 2A inhibits the cysteine protease papain in cross-class inhibition. This study demonstrates the novel finding that both the non-RSL NH(2)-domain and the RSL domain with P1-P1' residues participate in endopin 2A inhibition. Production of a chimeric mutant of endopin 2A with replacement of its NH(2)-domain with that of endopin 1 resulted in less effective inhibition of papain, indicated by its lower k(ass) association rate constant compared to wild-type endopin 2A. This chimeric mutant formed complexes with papain, but at lower levels compared to that with wild-type endopin 2A. Papain degradation of a portion of the chimeric mutant suggested a role for the NH(2)-domain in regulating relative amounts of endopin 2A that enter the substrate pathway compared to the serpin inhibitory pathway. Furthermore, site-directed mutagenesis demonstrated that the RSL domain with intact P1-P1' residues was necessary for inhibition. These findings indicate that the NH(2)-domain and the RSL region both participate in endopin 2A inhibition of papain.

摘要

丝氨酸蛋白酶抑制剂内肽酶2A在交叉抑制中可抑制半胱氨酸蛋白酶木瓜蛋白酶。本研究证明了一个新发现，即非反应中心环（RSL）的NH₂结构域和具有P1 - P1'残基的RSL结构域均参与内肽酶2A的抑制作用。用内肽酶1的NH₂结构域替换内肽酶2A的NH₂结构域产生的嵌合突变体，对木瓜蛋白酶的抑制效果较差，这表现为与野生型内肽酶2A相比，其较低的k(ass) 缔合速率常数。该嵌合突变体与木瓜蛋白酶形成复合物，但与野生型内肽酶2A相比水平较低。木瓜蛋白酶对部分嵌合突变体的降解表明，NH₂结构域在调节进入底物途径的内肽酶2A与丝氨酸蛋白酶抑制剂抑制途径的相对量方面发挥作用。此外，定点诱变表明具有完整P1 - P1'残基的RSL结构域对于抑制是必需的。这些发现表明，NH₂结构域和RSL区域均参与内肽酶2A对木瓜蛋白酶的抑制作用。

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FEBS Lett. 2006 Jun 12;580(14):3477-84. doi: 10.1016/j.febslet.2006.04.099. Epub 2006 May 15.
2
The novel bovine serpin endopin 2C demonstrates selective inhibition of the cysteine protease cathepsin L compared to the serine protease elastase, in cross-class inhibition.新型牛丝氨酸蛋白酶抑制剂内多芬2C在交叉类别抑制中，相较于丝氨酸蛋白酶弹性蛋白酶，对半胱氨酸蛋白酶组织蛋白酶L表现出选择性抑制作用。
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3
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Biochem Biophys Res Commun. 2005 Feb 18;327(3):837-44. doi: 10.1016/j.bbrc.2004.12.053.
4
Muscle endopin 1, a muscle intracellular serpin which strongly inhibits elastase: purification, characterization, cellular localization and tissue distribution.肌肉内源性蛋白酶抑制剂1，一种强烈抑制弹性蛋白酶的肌肉细胞内丝氨酸蛋白酶抑制剂：纯化、特性、细胞定位及组织分布
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