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血管生成素与α-辅肌动蛋白2相互作用的表征与功能

Characterization and Function of the Interaction of Angiogenin With Alpha-Actinin 2.

作者信息

Weng Chunhua, Dong Haojie, Mao Jiajia, Lang Xiabing, Chen Jianghua

机构信息

Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China.

出版信息

Front Mol Biosci. 2022 Apr 8;9:837971. doi: 10.3389/fmolb.2022.837971. eCollection 2022.

Abstract

Angiogenin (ANG) is the first human tumor-derived angiogenic protein, which can promote angiogenesis and tumor growth. In a previous study, we identified alpha-actinin 2 (ACTN2), a cytoskeletal protein, as a direct interacting protein with angiogenin. However, the interaction between ANG and ACTN2 was not characterized in detail, which may provide information on the molecular mechanisms of ANG functions. In this study, we mapped the accurate binding domain and sites in ANG and ACTN2, respectively. In ANG, the residues from 83 to 105 are the smallest motif that can bind to ACTN2. We then use site mutation analysis to identify the precise binding sites of ANG in the interaction and found that the 101st residue arginine (R101) represents the critical residue involved in the ANG-ACTN2 interaction. In ACTN2, the residues from 383 to 632, containing two spectrin domains in the middle of the rod structure of ACTN2, play an important role in the interaction. Furthermore, we validated the interaction of ACTN2-383-632 to ANG by glutathione-S-transferase (GST) pull-down assay. In functional analysis, overexpressed ACTN2-383-632 could impair tumor cell motility observably, including cell migration and invasion. Meanwhile, ACTN2-383-632 overexpression inhibited tumor cell proliferation and survival as well. These data suggest that an excess expression of ACTN2 segment ACTN2-383-632 can inhibit tumor cell motility and proliferation by interfering with the interaction between ANG and ACTN2, which provides a potential mechanism of ANG action in tumor growth and metastasis.

摘要

血管生成素(ANG)是首个从人类肿瘤中分离出的血管生成蛋白,可促进血管生成和肿瘤生长。在之前的一项研究中,我们鉴定出细胞骨架蛋白α-辅肌动蛋白2(ACTN2)是与血管生成素直接相互作用的蛋白。然而,ANG与ACTN2之间的相互作用尚未得到详细表征,这可能为ANG功能的分子机制提供信息。在本研究中,我们分别绘制了ANG和ACTN2中精确的结合结构域和位点。在ANG中,83至105位的残基是能够与ACTN2结合的最小基序。然后,我们通过位点突变分析确定了ANG在相互作用中的精确结合位点,发现第101位残基精氨酸(R101)是参与ANG-ACTN2相互作用的关键残基。在ACTN2中,383至632位的残基,在ACTN2杆状结构中间包含两个血影蛋白结构域,在相互作用中起重要作用。此外,我们通过谷胱甘肽-S-转移酶(GST)下拉试验验证了ACTN2-383-632与ANG的相互作用。在功能分析中,过表达的ACTN2-383-632可显著损害肿瘤细胞的运动能力,包括细胞迁移和侵袭。同时,ACTN2-383-632的过表达也抑制了肿瘤细胞的增殖和存活。这些数据表明,ACTN2片段ACTN2-383-632的过表达可通过干扰ANG与ACTN2之间的相互作用来抑制肿瘤细胞的运动和增殖,这为ANG在肿瘤生长和转移中的作用提供了一种潜在机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd25/9033276/bda7d74aa09f/fmolb-09-837971-g001.jpg

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