Scientists at the Van Andel Research Institute and the City University of New York have described the atomic-level structure of a molecular complex responsible for modifying proteins. They believe their work could lead to the development of new therapeutics for cancer and other diseases. 

The complex, known as OST, or oligosaccharyltransferase, plays an important role in protein glycosylation.

“The determination of the atomic-level structure of OST is a breakthrough in glycobiology,” said Huilin Li, Ph.D., a professor at Van Andel Research Institute (VARI) and senior author on a study (“The Atomic Structure of a Eukaryotic Oligosaccharyltransferase Complex”) published in Nature. “As a key enzyme in the N-linked glycan biosynthesis pathway, OST is important in both health and disease. We hope these findings will lead to life-changing therapies for cancer and many other disorders.”

“Our understanding of eukaryotic protein N-glycosylation has been limited owing to the lack of high-resolution structures. Here we report a 3.5-Å resolution cryo-EM structure of the Saccharomyces cerevisiae OST, revealing the structures of Ost1–5, Stt3, Wbp1, and Swp1. We found that seven phospholipids mediate many of the inter-subunit interactions, and an Stt3 N-glycan mediates interactions with Wbp1 and Swp1 in the lumen,” write the investigators.

OST structure. [Huilin Li Lab/Van Andel Research Institute]

“Ost3 was found to mediate the OST-Sec61 translocon interface, funnelling the acceptor peptide towards the OST catalytic site as the nascent peptide emerges from the translocon. The structure provides novel insights into co-translational protein N-glycosylation and may facilitate the development of small-molecule inhibitors targeting this process.”

Most proteins modified by OST are either secreted or become embedded in the cell's surface membrane, where they act as a conduit between the cell and its environment. Their exposure to the cell's surroundings and the presence of glycans make them ideal targets for new medications, which often use glycans' specific chemical signatures to zero in on a cancer cell, for example.

Although OST was discovered many decades ago, its structure remained unclear. The atomic structure of OST described in the Nature paper is from baker's yeast, a simple and elegant model for biomedical research. 

Unlike other complexes that are assembled by interactions between proteins, the eight membrane proteins that comprise OST are largely “glued” together by seven phospholipid molecules in the center of its structure, explained Dr. Li, adding that these lipids made the complex difficult to purify for structural analysis.

“The intricacy and novelty of OST's structure is truly remarkable,” said Lin Bai, Ph.D., a senior research scientist in Li's lab and first author on the paper. “The structure is the culmination of more than a decade of work and provides important clarity and insight into a common cellular process that affects half the proteins in the human body.” 

The structure suggests functional roles for its eight component proteins, which were recruited to the catalytic core enzyme over billions of years of evolution. Some of these proteins were found to recognize the donor substrate glycan or acceptor proteins, while others coordinate with protein synthesis and protein translocation machinery.

The structure also reveals key reaction sites that may be targeted by drugs designed to correct dysfunctions in diseases like cancer.

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