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靶向 HPV E6 癌蛋白的两个致癌功能位点的高亲和力双价配体。

Targeting the Two Oncogenic Functional Sites of the HPV E6 Oncoprotein with a High-Affinity Bivalent Ligand.

机构信息

Oncoprotein Team, Équipe Labellisée Ligue 2015, UMR CNRS-UDS 7242, École Supérieure de Biotechnologie de Strasbourg, Boulevard Sébastien Brant, BP 10413, F-67412 Illkirch (France).

IGBMC, 1 rue Laurent Fries, BP 10142, 67404 Illkirch (France).

出版信息

Angew Chem Int Ed Engl. 2015 Jun 26;54(27):7958-62. doi: 10.1002/anie.201502646. Epub 2015 May 27.

Abstract

The E6 oncoproteins of high-risk mucosal (hrm) human papillomaviruses (HPVs) contain a pocket that captures LxxLL motifs and a C-terminal motif that recruits PDZ domains, with both functions being crucial for HPV-induced oncogenesis. A chimeric protein was built by fusing a PDZ domain and an LxxLL motif, both known to bind E6. NMR spectroscopy, calorimetry and a mammalian protein complementation assay converged to show that the resulting PDZ-LxxLL chimera is a bivalent nanomolar ligand of E6, while its separated PDZ and LxxLL components are only micromolar binders. The chimera binds to all of the hrm-HPV E6 proteins tested but not to low-risk mucosal or cutaneous HPV E6. Adenovirus-mediated expression of the chimera specifically induces the death of HPV-positive cells, concomitant with increased levels of the tumour suppressor P53, its transcriptional target p21, and the apoptosis marker cleaved caspase 3. The bifunctional PDZ-LxxLL chimera opens new perspectives for the diagnosis and treatment of HPV-induced cancers.

摘要

高危黏膜(hrm)型人乳头瘤病毒(HPV)的 E6 癌蛋白含有一个口袋,可以捕获 LxxLL 基序和一个 C 末端基序,招募 PDZ 结构域,这两个功能对于 HPV 诱导的致癌作用至关重要。通过融合 PDZ 结构域和 LxxLL 基序构建嵌合蛋白,这两个结构域都已知与 E6 结合。NMR 光谱、量热法和哺乳动物蛋白互补测定结果表明,所得的 PDZ-LxxLL 嵌合体是 E6 的二价纳摩尔配体,而其分离的 PDZ 和 LxxLL 成分仅为微摩尔结合物。该嵌合体与所有测试的 hrm-HPV E6 蛋白结合,但不与低危黏膜或皮肤型 HPV E6 结合。腺病毒介导的嵌合体表达特异性诱导 HPV 阳性细胞死亡,同时增加肿瘤抑制因子 P53、其转录靶标 p21 和凋亡标志物 cleaved caspase 3 的水平。双功能 PDZ-LxxLL 嵌合体为 HPV 诱导癌症的诊断和治疗开辟了新的前景。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c2b0/4517096/4b3b7869a6a0/anie0054-7958-f1.jpg

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