点击次数：

论文类型：期刊论文

发表时间：2017-05-01

发表刊物：CHEMICAL BIOLOGY & DRUG DESIGN

收录刊物：SCIE、PubMed、Scopus

卷号：89

期号：5

页面范围：655-662

ISSN号：1747-0277

关键字：caffeic acid phenethyl ester; covalent binding; nuclear export; XPO1; CRM1

摘要：Caffeic acid phenethyl ester (CAPE) is the bioactive constituent of propolis from honeybee hives and is well known for its anti-inflammatory, anticarcinogenic, antioxidant, and immunomodulatory properties. Herein, we revisited the cellular mechanism underlying the diverse biological effects of CAPE. We demonstrated that XPO1/CRM1, a major nuclear export receptor, is a cellular target of CAPE. Through nuclear export functional assay, we observed a clear shift of XPO1 cargo proteins from a cytoplasmic localization to nucleus when treated with CAPE. In particular, we showed that CAPE could specifically target the non-catalytic and conserved Cys(528) of XPO1 through the means of mass spectrometric analysis. In addition, we demonstrated that the mutation of Cys(528) residue in XPO1 could rescue the nuclear export defects caused by CAPE. Furthermore, we performed position-restraint molecular dynamics simulation to show that the Michael acceptor moiety of CAPE is the warhead to enable covalent binding with Cys(528) residue of XPO1. The covalent modulation of nuclear export by CAPE may explain its diverse biological effects. Our findings may have general implications for further investigation of CAPE and its structural analogs.