Old Protein Gains New Senses

It is fairly common, even for many scientists, to be dismissive of carbohydrate molecules, mentioning them almost as an afterthought when describing normal cellular functions, especially since DNA and proteins constitute the bulk of the metabolic workload. However, there is one area where carbohydrates, specifically glycan structures, are indispensable: cell-cell recognition.

Differences in structure and bonding create glycan fingerprints that many cells use to determine if neighbors they come in contact with are friend or foe. This is not a new concept to biology and has been studied for many years, yet several key features in the recognition process have eluded scientists.

Now, a collaborative team lead by researchers from the University of Wisconsin-Madison has discovered a new ability of a well-studied protein, which resides within the lungs and intestines, to distinguish between human cells and bacterial cells. The scientists show that the protein, called intelectin-1, is able to selectively recognize glycan residues that reside on the surface of cells—illuminating a previously unrecognized line of defense against microbial invaders.

“This has the potential to change the game in terms of how we combat microbes,” said senior author Laura Kiessling, Ph.D., professor of chemistry and biochemistry at the University of Wisconsin-Madison.

The findings from this study were published today in Nature Structural and Molecular Biology “Recognition of microbial glycans by human intelectin-1.”

Intelectin was first isolated from the African clawed frog Xenopus laevis and found to be involved in embryonic development. Once the crystal structure was determined, scientists discovered that the protein contained carbohydrate recognition domains and observed its role in many cellular processes, such as tissue development and inflammation. However, the protein’s function in host-cell defense and ability to distinguish multiple types of pathogens is a new and exciting find.

“The protein is upregulated with infection,” explained Dr. Kiessling, “and while no one has yet shown that it is an antimicrobial protein, there are multiple lines of evidence that suggest it is.”

Dr. Kiessling and her colleagues were able to establish that intelectin has all the properties needed to function in the immune system's surveillance complex—a logical discovery as the protein is found mostly in the cells in the intestine and respiratory system, the two most likely entry points for microbial pathogens.

By exposing human intelectin to a collection of both human and microbial glycans, the Wisconsin researchers found that intelectin could recognize different kinds of microbes as well as distinguish between microbial and mammalian glycans. The investigators surmised that intelectin has evolved a role within the immune system over millions of years, as the protein has homologs in a wide array of vertebrates and invertebrates.

Interestingly, the glycans to which intelectin attaches can be immensely different. For example, in humans less than 35 chemical building blocks are used to make the cell surface molecules. Yet, bacteria have evolved to create more than 700 chemical building blocks for glycans. This immense increase in diversity can make accurate detection difficult.

“Human intelectin just recognizes a small portion of the glycan, a shared feature like a handle,” Dr. Kiessling stated. “Then it can recognize when the handles appear, even when different types of bacteria make different glycans.”

Dr. Kessling and her colleagues believe that future work in this area could aid in the rational design of novel therapeutics to thwart microbial infections, especially those becoming resistant to current medications.