Identification of a human estrogen receptor α-derived antiestrogenic peptide that adopts a polyproline II conformation
Identification of a human estrogen receptor α-derived antiestrogenic peptide that adopts a polyproline II conformation
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DOI：
10.1002/psc.1136
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发表时间：
2009-07-01
影响因子：
2.1
通讯作者：
Jacquot, Yves
中科院分区：
文献类型：
--
作者：
Kapitan, Josef;Gallo, Dominique;Jacquot, Yves
聚脯氨酸II（PPII）螺旋是存在于许多蛋白质中的延伸二级结构。含有PPII的序列介导与含有称为PPII识别结构域（PRD）的适当同源结构域的伴侣的特异性蛋白质-蛋白质相互作用，并且参与细胞内信号传导途径的激活。因此，蛋白质中PPII结构的鉴定具有极大的意义，不仅可以探索分子和生理机制，还可以开发新的潜在药物。通过重新研究配体α型人雌激素受体（ER α）的X射线晶体结构，我们在受体的配体结合结构域中鉴定了一个11个残基的PPII螺旋序列（D（321）AEPPILYSEY（331））。通过远紫外圆二色性（far-UV CD）、振动拉曼光学活性（罗阿A）和差示扫描量热法（DSC）记录的数据显示，相应的肽（Ac-DAEPPILYSEY-NH 2）在PPII中特别好地结构化，具有与从X射线结构观察到的PPII相同的比例（类似于85%）。此外，在用pcDNA 3-ER α质粒和Vit-tk-Luc报告基因瞬时共转染的ER α阴性Evsa-T乳腺癌细胞上进行的研究显示，该肽拮抗雌二醇诱导的转录，为研究具有拮抗性质的新分子提供了前景。版权所有（C）2009欧洲肽协会和约翰威利父子有限公司。
Polyproline II (PPII) helix is an extended secondary structure present in a number of proteins. PPII-containing sequences mediate specific protein-protein interactions with partners containing appropriate cognate domains called PPII-recognizing domains (PRDs) and are involved in the activation of intracellular signaling pathways. Thus, the identification of PPII structures in proteins is of great interest, not only to explore molecular and physiological mechanisms, but also to elaborate new potential drugs. By revisiting X-ray crystal structures of liganded alpha-type human estrogen receptor (ER alpha), we have identified an 11-residue PPII-helical sequence (D(321)AEPPILYSEY(331)) in the ligand-binding domain of the receptor. The data recorded by far-ultraviolet circular dichroism (far-UV CD), vibrational Raman optical activity (ROA) and differential scanning calorimetry (DSC) show that the corresponding peptide (Ac-DAEPPILYSEY-NH2) is particularly well structured in PPII, with the same proportion of PPII as observed from X-ray structures (similar to 85%). In addition, studies carried out on ER alpha-negative Evsa-T breast cancer cells transiently co-transfected with a pcDNA3-ER alpha plasmid and a Vit-tk-Luc reporter gene revealed that the peptide antagonizes the estradiol-induced transcription providing perspectives for researching new molecules with antagonistic properties. Copyright (C) 2009 European Peptide Society and John Wiley & Sons, Ltd.