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[2020/07/23]A Publication by Professor Huang of the Institute of Biochemistry and Molecular Biology in Nature Communications Changes Our Understanding of the Protein Galectin

NYMU Institute of Biochemistry and Molecular Biology Professor Huang and his team have changed our understanding of the protein Galectin and this should help provide a new direction for future drug development.

 

Lectins are common glycogen binding proteins and many biological phenomena require that glycogen binds to a lectin, including control of immune responses and cancer metastasis. This binding has allowed scientists to design drugs targeting this type of protein. Research at NYMU has discovered that the non-structural region within the lectin galetin-3, rather than the structural region, is the key to agglutination. This rewrites what is known about galetin-3 in the scientific literature and provides a new direction for future drug development.

 

Among the various lectins that are known, galectin-3 has been considered by many scientists to be involved in inflammation and various neurodegenerative diseases. These diseases include Huntington disease, Alzheimer’s disease and even some cancers. If we can block the molecular mechanism by which galectin-3 acts, this should help the treatment of these diseases. However, galectin-3 contains a long non-structural protein region known as a “disordered protein.” Due to its unknown structure, this region has been ignored in the past and therefore the function of this non-structural protein segment remained a mystery.

 

After five years of effort, Professor Huang of the National Yang-Ming University Institute of Biochemistry and Molecular Biology has discovered how galectin-3 utilizes twelve key tryptophan and tyrosine residues within the non-structural region to achieve liquid-liquid phase separation. This helps to answer the question as to why more than half of the proteins in our body are without structure or have a non-structural region.

 

     

  A structural protein (left) and a non-structural protein (right)

 

Scientists have learned in recent years that a disordered protein structure can help proteins within cells undergo liquid-liquid phase separation, as well as helping them to decide whether to aggregate or go into solution in response to the environment. Professor Huang’s discovery not only explains gelatin-3's functionality, but also how agglutination of disordered proteins occurs outside the cell. This will allows scientists to create therapies that specifically target a disordered protein region and inhibit agglutination, which should help the treatment of relevant diseases.

 

Professor Huang remarked that galectin-3 was chosen from among many lectins as the research objective because it is an exception within this protein family. The other members of this protein family have a complete dimer or tandem structure, but galectin-3 has neither. Its structural segment is particularly long, which means that it can be used to verify the function of the disordered protein segment and help identify the overall functions of the whole protein in the human body.

 

The research team compared the protein sequences of galectin from humans, rabbits, mice, dogs, pigs, birds and fish; they discovered that the non-structural segment is different across the species, but nevertheless the region is conserved. This implies that, from low-order species to high-order species during evolution, the disordered region must have retained and conserved some specific function. The research team used a range of techniques, including point mutations, nuclear magnetic resonance spectroscopy, and microscopy and found that the disordered segments of multiple galectin-3 proteins are able to aggregate together lipopolysaccharide micelles to form larger aggregates. This confirmed the fact that this protein is using its disordered segments to bring about agglutination.

 

Huang remarked that the galectin family is large, and the structural segments of its member proteins are very similar. Drugs designed to target structural parts of these proteins may thus suffer from "targeting errors" and affect multiple types of lectins; this means these drugs cannot be used as a precise treatment. Once they found out that galectin-3 is able to aggregate via its non-structural segments, it is now possible to design drugs that targeting these regions, which will improve their efficacy and reduce their side effects.

 

Team members, (left) MSc student Sun, Professor Huang; (right) Professor Guo and MSc student Chiu

 

This research has involved four MSc students, Lin Yu-hao, Chiu De-chen, Chiu Yi-ping, and Sun Yong-chen. It took a total of five years to complete the research, and the latter two students have shared honor of being the first authors on the paper. The results were published in Natural Communications. Huang expressed his gratitude for his students' enthusiasm in the pursuit of science truth and affirmed their strong commitment to the research. In addition, he would also like to thank Professor Guo, Professor Wang, Academian Liu of Academica Sinica, and Dr. Chang of the High Magnetic Field Nuclear Magnetic Resonance Center for their assistance with this research.

 

 

 

 

 

 

 

 

 

 


 

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