解码ATXN2磷码:结构洞察和疾病治疗机会。

IF 1.4 4区 生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
Apoorva Pai Kalasa Anil Kumar, Suhail Subair, Prathik Basthikoppa Shivamurthy, Samseera Ummar, Athira C. Rajeev, Rajesh Raju
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引用次数: 0

摘要

Ataxin-2 (ATXN2)是一种关键的RNA结合蛋白,调节RNA代谢、应激颗粒形成和神经元稳态,磷酸化失调导致脊髓小脑性共济失调2型(SCA2)、肌萎缩侧索硬化症(ALS)和癌症。本文综合了结构生物学、磷酸化蛋白质组学和相互作用组学分析,绘制了ATXN2内在无序区域的6个关键磷酸化位点(S772、T741、S624、S684、S784、S889)。这些位点受激酶GSK3β、CDK13和磷酸酶如INPP5F的调节,协调与rna结合伙伴(如ATXN2L、FXR2、STAU2)和共调节蛋白(如TP53BP1、NUP153)的相互作用,通过破坏自噬、核胞质转运和应激颗粒动力学驱动发病机制。我们提出了靶向治疗,包括针对ALS的GSK3β抑制剂,针对SCA2的反义寡核苷酸和针对癌症的MTOR调节剂,以恢复ATXN2功能。通过阐明ATXN2的磷酸化编码,本工作为神经退行性疾病和肿瘤疾病的精准医学提供了新的途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Decoding ATXN2 Phosphocode: Structural Insights and Therapeutic Opportunities in Disease

Ataxin-2 (ATXN2), a key RNA-binding protein, regulates RNA metabolism, stress granule formation, and neuronal homeostasis, with dysregulated phosphorylation contributing to Spinocerebellar Ataxia type 2 (SCA2), amyotrophic lateral sclerosis (ALS), and cancer. This review integrates structural biology, phosphoproteomics, and interactome analyses to map six critical phosphosites (S772, T741, S624, S684, S784, S889) within ATXN2’s intrinsically disordered regions. Modulated by kinases GSK3β and CDK13 and phosphatases like INPP5F, these sites orchestrate interactions with RNA-binding partners (e.g., ATXN2L, FXR2, STAU2) and co-regulated proteins (e.g., TP53BP1, NUP153), driving pathogenesis through disrupted autophagy, nucleocytoplasmic transport, and stress granule dynamics. We propose targeted therapies, including GSK3β inhibitors for ALS, antisense oligonucleotides for SCA2, and MTOR modulators for cancer, to restore ATXN2 function. By elucidating phosphocode of ATXN2, this work highlights novel avenues for precision medicine in neurodegenerative and oncogenic diseases.

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来源期刊
The Protein Journal
The Protein Journal 生物-生化与分子生物学
CiteScore
5.20
自引率
0.00%
发文量
57
审稿时长
12 months
期刊介绍: The Protein Journal (formerly the Journal of Protein Chemistry) publishes original research work on all aspects of proteins and peptides. These include studies concerned with covalent or three-dimensional structure determination (X-ray, NMR, cryoEM, EPR/ESR, optical methods, etc.), computational aspects of protein structure and function, protein folding and misfolding, assembly, genetics, evolution, proteomics, molecular biology, protein engineering, protein nanotechnology, protein purification and analysis and peptide synthesis, as well as the elucidation and interpretation of the molecular bases of biological activities of proteins and peptides. We accept original research papers, reviews, mini-reviews, hypotheses, opinion papers, and letters to the editor.
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