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中文- Update Date：2025-01-07
- Units：Office of International Promotion and Outreach
Proteins Assemble Like Superheroes? NYCU Research on “Proteins with IDRs” Offers New Hope for Neurodegenerative Diseases
(Photo credit: Getty Images)
Translated by Chance Lai
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Can proteins assemble in response to a call like superheroes? A research team at the Institute of Biochemistry and Molecular Biology at National Yang Ming Chiao Tung University (NYCU) has uncovered how proteins with intrinsically disordered regions (IDRs), despite their lack of fixed structure, aggregate in a highly regulated manner.
Driven by changes in environmental pH, this process reveals new molecular mechanisms with promising implications for neurodegenerative disease treatments. This study, published in the prestigious journal Advanced Science, opens the door to potential drug targets and therapeutic strategies.
Proteins with IDRs: Dynamic Executors of Cellular Functions
The research highlights Galectin-3, a protein pivotal in lysosome repair and a key marker of cellular damage. Abnormal aggregation of Galectin-3 has been closely linked to neurodegenerative diseases, but its underlying mechanisms were not well understood until now.
The team, led by Professor Jie-Rong Huang, demonstrated that Galectin-3 adjusts its aggregation behavior based on intracellular pH levels. Specific interactions within the protein structure mediate this regulation: positively charged residues in the protein’s folded domain interact with aromatic residues in its IDR via cation–π interactions, while π–π interactions occur between IDRs. Additionally, two negatively charged residues in Galectin-3’s IDR serve as pH-sensitive “safety valves,” fine-tuning the protein’s tendency to condense and preventing excessive aggregation.
These findings offer new insights into how electrostatic and molecular interactions regulate the delicate balance between disordered and structured regions of proteins, shedding light on previously unrecognized mechanisms.
Driven by changes in environmental pH, this process reveals new molecular mechanisms with promising implications for neurodegenerative disease treatments. This study, published in the prestigious journal Advanced Science, opens the door to potential drug targets and therapeutic strategies.
Proteins with IDRs: Dynamic Executors of Cellular Functions
The research highlights Galectin-3, a protein pivotal in lysosome repair and a key marker of cellular damage. Abnormal aggregation of Galectin-3 has been closely linked to neurodegenerative diseases, but its underlying mechanisms were not well understood until now.
The team, led by Professor Jie-Rong Huang, demonstrated that Galectin-3 adjusts its aggregation behavior based on intracellular pH levels. Specific interactions within the protein structure mediate this regulation: positively charged residues in the protein’s folded domain interact with aromatic residues in its IDR via cation–π interactions, while π–π interactions occur between IDRs. Additionally, two negatively charged residues in Galectin-3’s IDR serve as pH-sensitive “safety valves,” fine-tuning the protein’s tendency to condense and preventing excessive aggregation.
These findings offer new insights into how electrostatic and molecular interactions regulate the delicate balance between disordered and structured regions of proteins, shedding light on previously unrecognized mechanisms.
The aggregation patterns of proteins with intrinsically disordered regions (IDRs) in a pH 7 environment were observed under an optical microscope.
Balancing Aggregation: From Cellular Harmony to Disease
Despite their lack of fixed structure, proteins with IDRs display remarkable functional flexibility. Under normal conditions, they form regulated assemblies to collaborate with other proteins and perform essential cellular tasks. However, abnormal aggregation can disrupt this balance, leading to disease. For example, Galectin-3’s unregulated aggregation may contribute to amyloid plaque formation, accelerating the progression of neurodegenerative disorders such as Alzheimer’s.
By identifying the charge-driven mechanisms governing protein aggregation, this research advances the understanding of IDR-associated proteins and reveals potential therapeutic strategies. Future treatments may exploit these regulatory pathways to prevent harmful protein aggregation in neurodegenerative diseases.
Young Scholars Pioneering Breakthroughs
Professor Jie-Rong Huang (left) with his research team: PhD student Yung-Chen Sun (center) and Master’s student Tzung-Lun Hsieh (right).The study was co-authored by NYCU graduates Yung-Chen Sun and Tzung-Lun Hsieh, who contributed as joint first authors. Both researchers began their journeys as undergraduates in Professor Huang’s lab, gaining significant experience in cutting-edge molecular biology. Their work highlights the innovative power of young scientists and underscores the importance of fostering early research opportunities.
This study illuminates the intricate order hidden within the “disordered” realm of proteins with IDRs. As superheroes assemble to protect the world, these proteins respond to specific cues to maintain cellular function and stability. Their ability to aggregate and disaggregate in response to environmental changes highlights their essential role in cellular health.
Looking ahead, these “disordered heroes” may unlock transformative advancements in medicine, offering new hope for combating devastating diseases through innovative therapeutic interventions.
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