Decoding ATXN2 Phosphocode: Structural Insights and Therapeutic Opportunities in Disease.

Apoorva Pai Kalasa Anil Kumar, Suhail Subair, Prathik Basthikoppa Shivamurthy, Samseera Ummar, Athira C Rajeev, Rajesh Raju

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Review in The protein journal, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 · Who and what money

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6 authors.

Apoorva Pai Kalasa Anil KumarYenepoya University, Mangalore, India.

Suhail SubairYenepoya University, Mangalore, India.

Prathik Basthikoppa ShivamurthyYenepoya University, Mangalore, India.

Samseera UmmarYenepoya University, Mangalore, India.

Athira C RajeevYenepoya University, Mangalore, India. athiracr.ciods@yenepoya.edu.in.

Rajesh RajuYenepoya University, Mangalore, India. rajeshraju@yenepoya.edu.in.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

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.

Indexed as

Amyotrophic Lateral SclerosisAtaxin-2NeoplasmsSpinocerebellar AtaxiasAnimalsGlycogen Synthase Kinase 3 betaHumansPhosphorylationAtaxin-2ATXN2 protein, humanGlycogen Synthase Kinase 3 betaAmyotrophic lateral sclerosisAtaxin-2PhosphoproteomicsSpinocerebellar Ataxia type 2

Identifiers

PMID40884740

DOI10.1007/s10930-025-10287-4

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