New MIT study converts glucose transporter into water-soluble form

All cell membranes in the human body contain proteins that act as sensors, messengers, or tools for transporting and regulating substances in and out of cells. Transport proteins, in particular, are poorly understood due to their structural complexity and hydrophobic nature, making them difficult to study. At the same time, these transporters, especially those that regulate glucose, play a crucial role in the growth of cancerous tumors.

In a new study, scientists led by MIT Shuguang Zhang, Ph.D., demonstrate a method to rapidly predict the structural design of hydrophilic variants of 14 glucose-transporting membrane proteins in cells. This will make it easier for researchers to study proteins in water. The scientists confirmed their accuracy by comparing the predicted structures to existing crystal images of the two proteins.

They hope that better understanding of these glucose transporters will lead to the development of monoclonal antibodies to treat cancer metastasis. This actually starves cancer cells by blocking glucose transporters.

Eva morodina, Structural Biologist at the Griff Laboratory at the University of Oslo and lead author of the paper on the study, said: "Most cancer cells significantly increase the expression and production of glucose transporters (GLUTs) because they have unmet energy demand." "There are currently few effective drugs to stop the oversupply because of their challenging structure."

The complex structure of GLUTs includes 12 transmembrane hydrophobic helices embedded in the membrane. In their native or crystalline state, the hydrophobic structures must be placed in special detergents or reagents studied in the laboratory, or they will lose their structure. The structure and function of proteins are indelibly linked.

"Studying these proteins in detergents is like assembling expensive watches or playing violins with heavy gloves," Dr. Shuguang Zhang said. He began studying membrane proteins in the early 2000s. "Few people have studied these membrane proteins," Dr. Shuguang Zhang said. "They're like hot potato."

The new work was based on the success four years ago, when he and a team completed his nearly a decade of work: they designed a very simple method called the QTY code to convert hydrophobic cell membrane proteins into hydrophilic proteins by replacing many hydrophobic amino acids.

QTY codes are named after three amino acids, glutamine (Q), threonine (T), and tyrosine (Y), which replace four hydrophobic amino acids: leucine (L), isoleucine (I), valine (V), and phenylalanine (F). None of these amino acids are charged, so this substitution is benign. Structures are essential for protein function and substitution does not alter the structure.

In the latest study, Dr. Shuguang Zhang and their team applied the QTY encoding to 14 glucose-transporting membrane proteins that transport sugars into cells. They used the new AlphaFold2 program, an artificial intelligence-based computational program developed by DeepMind that can accurately and quickly predict how proteins fold. The researchers used the QTY code and the open-source AlphaFold2 to predict the alpha-helix shapes of 14 GLUT proteins, including their natural hydrophobic shapes and their water-soluble shapes altered by their QTY codes.

The crystalline or natural-state structures of two of the GLUTs (1 and 3) have been previously revealed by other researchers using x-ray crystallography. To confirm their own method, Zhang's team first predicted the hydrophilic structures of the two GLUTs by applying QTY-encoded amino acid substitutions and letting AlphaFold2 predict the shape of the protein. It does it very accurately. The synthesized hydrophobic and hydrophilic images are almost identical.

The team then combined the QTY code and AlphaFold2 to predict the hydrophilic structures of 12 other GLUTs in record time. "In 2018, it took four to five weeks to simulate any protein structure with a high-speed computer cluster, now with AlphaFold2, we have free access to Google Computer, which can simulate transmembrane proteins in hours. Some small proteins take less than one hour."

Robert Langer, a professor at the Massachusetts Institute of Technology (MIT) who has been praised for his work in biomedical engineering, said: "This paper is excellent and I believe it has the potential to help many cancer patients." Professor Langer did not participate in this study.

The researchers say hope, but this is not part of the current study, that future studies will be able to genetically change glucose across the membrane to develop new therapeutic targets.

"Now our only options for treating cancer are surgery, chemotherapy or small molecule therapy. In the future, it is possible to obtain t-cells from patients, which are components of the immune system, and genetically engineer them in the laboratory so that they work almost like cancer search GPS systems and have the ability to attack tumors."

Collected by CD BioGlyco, a biotechnology company that has developed complete Carbohydrate Metabolism Analysis solutions, providing glucose analysis services in fruits, vegetables, nectar, cheese, and more.

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