Gunnar Reiske/Sandbox 102

Gluten Protein Complex

Function

The gluten protein complex is made up of gliadin and glutenin components. Of the complex, gliadin directly affects the induction of an innate immune response via the proline and glutamine peptide sequences. In the small intestine of patients with celiac disease, HLA-DQ2 restricted T-cells are present. After ingestion of a gluten product, the gliadin peptides enter the circulatory system and come into contact with lymphocytes and the gliadin-specific, HLA-DQ2 restricted T-cells, which is the fundamental step in producing the inflammatory response associated with celiac disease.^[2]

Relevance

Human leukocyte antigens (HLA) are responsible for regulation of the immune system. The binding of gliadin peptides to HLA should be the same in celiac and non-celiac patients. However, it is unclear why only specific individuals produce the gliadin-specific, HLA-DQ2 restricted T-cells with pathogenic consequences. These implications suggest an underlying genetic component. ^[3]

Immune Response

HLA-DQ2 and HLA-DQ8

Interactions

The HLA-DQ2 protein complex binds to the gluten complex through the use of hydrogen bonds via oxygen and nitrogen. The proline amino acids are all exposed to the external environment and do not participate in hydrogen binding. Only proline rich complexes are able to hydrogen bind properly with HLA-DQ2, such as gliadin. All other proteins do not have the proper conformation and organization of proline to effectively bind HLA-DQ2.^[4]

When the gluten peptide enters the HLA-DQ8 antigen binding cleft and makes contact, numerous contacts are made.^[5] Notable contacts include: 16 direct hydrogen bonds, 24 water mediated hydrogen bonds, and four salt bridges. The side chains of two glutamic acids and one phenylalanine buried deep in pockets of the complex serve to anchor the peptide within the antigen-binding groove. A proline and serine can be found in shallow pockets with their side chain serving as minor anchor residues to the peptide.

Treatments

Prolyl endopeptidases (PEPs) are a family of serine protease enzymes that help accelerate the breakdown of proline residues in peptides. Since gluten is a proline-rich complex, these enzymes can be used to help treat individuals with celiac disease. ^[6]

A study was done to explore the structural features of two bacterial PEPs, one with a bound enzyme and one without (Figure 1). Both PEPs have two domains: one that is the catalytic binding site and one called the propeller domain. With further investigation of domain features of the PEP isolated from Myxococcus xanthus, interactions were observed that give the enzyme its proline-cleaving properties (Figure 2).

Using the structural components of the open and bound forms of PEP enzymes, a mechanism was proposed in which the incoming proline-rich peptide causes a conformational change that opens the catalytic binding site. This conformation is stabilized by the prolines in the substrate interacting with the arginine and aspartate residues in the binding site. The propeller region does not interact with the bound substrate, but the aspartates and glutamate residues interact with arginine residues in the catalytic region to stabilize the unbound form of the enzyme.

Bacterial PEPs can detoxify immunotoxic proline-rich peptides in gut lumen of celiac patients by breaking down the gliadin before it reaches the small intestines. Given orally as a therapeutic treatment for those with celiac disease. Further research would need to be done on how we can make these enzymes more acid-stable to withstand the acidic environment of the human intestine. ^[7]

Studies have been done to determine the feasibility of the therapeutic implementation of bacterial PEP’s for detoxification of gliadin complexes in individuals with celiac disease. The study showed that a substantially high concentration of PEP’s as well as long exposure times (3 hours) were required for a complete detoxification of gliadin peptides and thus prevent intestinal transport of the peptides. ^[8]

Structural highlights

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