Swedish researchers discover new features for key protein in intestinal mucus

Researchers at the University of Gothenburg in Sweden have achieved a deeper understanding of the chemical structure of intestinal mucus, a key part of the body’s innate immune system. 

The 10-member team at the Department of Medical Biochemistry examined the structure of a protein, FCGBP (Fc gamma binding protein), a major component of the intestinal mucus in both mice and humans. 

Their report appears in the Journal of Biological Chemistry in July 2021. 

If you zoomed in on a sample of intestinal mucus, you would observe a complex network of proteins called mucins. These include the abundant MUC2 protein, the main structural component of mucus, whose job it is to keep bacteria and undigested food peptides at a distance from the wall of the gut. 

What is FCGBP?

The protein FCGBP is as abundant in mucus as MUC2, but its function is not clearly understood. To understand what these researchers discovered, let’s look a little more closely at FCGBP.

FCGBP is known as an IgGFc-binding protein. IgG is immunoglobulin G, the most abundant of the five classes of antibodies the body produces. These Y-shaped molecules are responsible for binding to and inactivating foreign substances such as pathogens and toxins. One of the three main regions on the Y-shape is known as the Fc (fragment crystallizable) region. Once an antibody has bound to an invading substance, it attracts immune system cells that destroy the captured invader. The Fc region is where these other immune system cells attach. 

Because FCGBP has this binding region, it had been thought that it might contribute to mucosal protection by binding immunoglobulins, which could trip HIV. However, the Swedish researchers report that they “were unable to reproduce this binding in vitro using purified proteins.” 

Instead, the researchers discovered a structural feature of FCGBP that was not known before. 

Human and mouse FCGBP contain repeated sequences of amino acids known as von Willebrand D (vWD) domains. These von Willebrand domains are usually involved in adhesive molecular interactions (such as sticking platelets together to cause blood to clot). 

The amino acid sequence found in these vWD domains is glycine-aspartic acid-proline-histidine, abbreviated GDPH. 

Cleavage site discovered

What the authors discovered is that the FGCBP protein is cut apart at these von Willebrand D sites by a process known as autocatalytic cleavage. However, this does not break up the protein as it remains connected by other chemical bonds known as disulfide bridges. 

As their experiments showed that these disulfide-stabilized molecules “do not seem to bind other proteins,” the question remains what is the main function of this protein that is so abundant in mucus.

The great abundance,” the authors suggest, “could indicate a function related to mucus gel formation and the single disulfide bond . . . could mediate controlled dissociation or rearrangement of the molecule depending on environmental factors.” 

“Further studies are needed to understand the functional role of this mucus protein,” they conclude.

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Ehrencrona et al. The IgGFc-binding protein FCGBP is secreted with all GDPH sequences cleaved but maintained by interfragment disulfide bonds, Journal of Biological Chemistry (July 2021). 

DOI: https://doi.org/10.1016/j.jbc.2021.100871