Impact of a Single Nucleotide Polymorphism on the 3D Protein Structure and Ubiquitination Activity of E3 Ubiquitin Ligase Arkadia.
Impact of a Single Nucleotide Polymorphism on the 3D Protein Structure and Ubiquitination Activity of E3 Ubiquitin Ligase Arkadia.
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DOI：
10.3389/fmolb.2022.844129
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发表时间：
2022
影响因子：
5
通讯作者：
Spyroulias GA
中科院分区：
文献类型：
--
作者：
Birkou M;Raptis V;Marousis KD;Tsevis A;Bourikas K;Bentrop D;Episkopou V;Spyroulias GA
单核苷酸多态性（single nucleotide polymorphisms，SNPs）是一种在人类健康研究中起重要作用的遗传变异。SNP研究通常用于识别与疾病相关的点突变。Arkadia（RNF 111）是一种E3泛素连接酶，通过靶向负调节因子降解来增强转化生长因子-β（TGF-β）信号传导。TGF-β途径的失调与癌症有关，因为它在正常细胞中表现出肿瘤抑制活性，而在肿瘤细胞中它促进侵袭和转移。SNP CGT > TGT在Arkadia的酶促RING结构域上产生精氨酸957至半胱氨酸的氨基酸（aa）取代。这在结直肠癌患者的肿瘤中比在正常组织样本中更普遍。这促使我们研究这种突变对Arkadia RING结构和活性的影响。我们使用核磁共振（NMR）在原子水平上分析R957 C Arkadia RING结构域的结构和动力学特性，而泛素化和荧光素酶测定提供了有关其酶功能的信息。我们的研究表明，R957 C突变改变了RING结构域的静电性质，但对其核心区的结构没有显着影响。然而，功能研究表明，R957 C Arkadia表现出显著增加的酶活性，支持文献数据，即肿瘤细胞内的Arkadia促进侵袭性和转移性行为。
Single nucleotide polymorphisms (SNPs) are genetic variations which can play a vital role in the study of human health. SNP studies are often used to identify point mutations that are associated with diseases. Arkadia (RNF111) is an E3 ubiquitin ligase that enhances transforming growth factor-beta (TGF-β) signaling by targeting negative regulators for degradation. Dysregulation of the TGF-β pathway is implicated in cancer because it exhibits tumor suppressive activity in normal cells while in tumor cells it promotes invasiveness and metastasis. Τhe SNP CGT > TGT generated an amino-acid (aa) substitution of Arginine 957 to Cysteine on the enzymatic RING domain of Arkadia. This was more prevalent in a tumor than in a normal tissue sample of a patient with colorectal cancer. This prompted us to investigate the effect of this mutation in the structure and activity of Arkadia RING. We used nuclear magnetic resonance (NMR) to analyze at an atomic-level the structural and dynamic properties of the R957C Arkadia RING domain, while ubiquitination and luciferase assays provided information about its enzymatic functionality. Our study showed that the R957C mutation changed the electrostatic properties of the RING domain however, without significant effects on the structure of its core region. However, the functional studies revealed that the R957C Arkadia exhibits significantly increased enzymatic activity supporting literature data that Arkadia within tumor cells promotes aggressive and metastatic behavior.
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影响因子：
11.2
作者：
Le Scolan, Erwan;Zhu, Qingwei;Luo, Kunxin
通讯作者：
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影响因子：
64.5
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作者：
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通讯作者：
Gronenborn, AM
影响因子：
2.9
作者：
Baker, KA;Hilty, C;Choe, S
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