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PolyQ Expansion Controls Biomolecular Condensation and Aggregation of the N-Terminal Fragments of Ataxin-2
Yin-Hu Liu1,2, Heng-Tong Duan1,2, Lei-Lei Jiang1
1Key Laboratory of RNA Innovation, Science and Engineering, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
Abstract:
Ataxin-2 (Atx2) is a general RNA-binding protein involved in processes such as RNA processing and metabolism in cells. Atx2 is also a polyglutamine (polyQ) tract-containing protein; its abnormal expansion can lead to protein aggregation associated with neurodegenerative diseases. Previous studies have shown that the C-terminal intrinsically disordered regions (c-IDRs) of Atx2 participate in its condensation and aggregation processes. To elucidate the role of polyQ expansion in biomolecular condensation and aggregation, we studied the N-terminal fragments of Atx2 (namely, Atx2-N317 and Atx2-N81) that preserve a polyQ tract and compared their molecular behaviors in cells to those of the full-length Atx2. We found that the molecular mobility of the N-terminal fragments decreases with the increasing length of polyQ, indicating that polyQ expansion promotes a gradual phase transition to an irreversible and insoluble state. Moreover, the molecular state and mobility of Atx2-N317 are not distinct from those of Atx2-N81, regardless of the presence of other domains, demonstrating that the polyQ tract is a direct and sufficient element for protein condensation and aggregation, while the Like Sm (LSm) and LSm-associated (LSmAD) domains and their interactions with RNA are not necessary for these processes. This result is also validated through the in vitro investigation of Atx2-N81 with different polyQ expansions. This study reveals that polyQ expansion controls the biomolecular condensation and aggregation of the N-terminal fragments of Atx2 and is thus thought to modulate the dynamic behaviors of the full-length protein as well, which is implicated in the pathological accumulation of Atx2 in cells.
Insights
Polyglutamine (polyQ) expansion in Ataxin-2 (Atx2) drives protein condensation and aggregation, independent of other domains. This finding is crucial for understanding neurodegenerative diseases linked to Atx2 accumulation.
Area of Science:
- Molecular Biology
- Neuroscience
- Biochemistry
Background:
- Ataxin-2 (Atx2) is an RNA-binding protein implicated in RNA processing and metabolism.
- Abnormal expansion of its polyglutamine (polyQ) tract is linked to neurodegenerative diseases due to protein aggregation.
- The C-terminal intrinsically disordered regions (c-IDRs) of Atx2 are known to participate in its condensation and aggregation.
Purpose of the Study:
- To elucidate the specific role of polyQ expansion in the biomolecular condensation and aggregation of Ataxin-2.
- To compare the cellular behavior of N-terminal Atx2 fragments with varying polyQ lengths to full-length Atx2.
- To determine if the polyQ tract alone is sufficient for Atx2 condensation and aggregation.
Main Methods:
- Studied N-terminal fragments of Ataxin-2 (Atx2-N317 and Atx2-N81) preserving the polyQ tract.
- Compared molecular behaviors of fragments and full-length Atx2 in cellular models.
- Conducted in vitro investigations of Atx2-N81 with varying polyQ expansions.
- Assessed molecular mobility and state of Atx2 fragments.
Main Results:
- Decreased molecular mobility of Atx2 fragments correlated with increased polyQ tract length, indicating a phase transition to an irreversible state.
- The polyQ tract was identified as a direct and sufficient element for protein condensation and aggregation.
- The Like Sm (LSm) and LSm-associated (LSmAD) domains, and RNA interactions, were found not necessary for these processes.
Conclusions:
- Polyglutamine expansion directly controls the biomolecular condensation and aggregation of Ataxin-2.
- The polyQ tract is the primary driver of Atx2 aggregation, independent of other domains or RNA interactions.
- These findings suggest polyQ expansion modulates Atx2's dynamic behavior, contributing to its pathological accumulation in neurodegenerative diseases.
