In the human immune system, the major histocompatibility complex (mhc-1) is very complex for antigen processing. How these proteins perform their key functions has not been well understood.

Now, researchers at the University of California, Santa Cruz, have figured out the details of the key molecular interactions associated with mhc-1 protein selection and antigen processing.

The new findings, published in the December 3 issue of PNAs, help to explain the differences between different mhc-1 proteins and have implications for understanding autoimmune diseases and immune responses to infection and cancer. The results also suggest that mhc-1 protein can be manipulated in the laboratory for diagnostic and therapeutic applications.

Nikolaos sgourakis, assistant professor of chemistry and biochemistry at the University of California, Santa Cruz and author of the paper, said: "our discovery of these basic mechanisms enables us to develop technologies with great potential for diagnosis and treatment."

The role of mhc-1 protein is to enable every cell in the body to display on its surface fragments of all the proteins (about 10000 different proteins) that are being produced in the cell. The peptide segments of mhc-1 protein displayed on the cell surface are recognized by cytotoxic T cells, which can recognize foreign proteins from pathogens or mutant proteins produced by tumor tissue and make immune response.

Sgourakis and his team worked closely with Erik procko's team at the University of Illinois to understand the mechanism of peptide selection and binding to MHC-I proteins. This new paper reveals how the interaction between mhc-1 protein and molecular chaperones affects the composition of displayed antigens.

There are thousands of different variants of human mhc-1 protein, which are produced by different "alleles" of mhc-1 gene. The variability of mhc-1 protein is the cause of many individual differences in immune response, including the differences in sensitivity to autoimmune diseases, infection and cancer. Everyone has six major mhc-1 alleles (three from mothers and three from fathers).

"Our six MHC-I proteins are capable of loading all possible peptides in cells," sgourakis said. These "barcodes" they chose became the antigen library, and each person's antigen library was different. "

Sgourakis' team studied four different MHC-I alleles and their interactions with molecular chaperones and antigens. One of the functions of molecular chaperones is to help mhc-1 proteins fold into their active shapes and stabilize them to prevent misfolding and aggregation. However, only some mhc-1 alleles rely on chaperones for antigen loading.

In this paper, nuclear magnetic resonance (NMR) was used to reveal the dynamic structural changes in mhc-1 protein. "We have obtained the static crystal structure of MHC protein, but we can't understand why some molecules depend on chaperones, while others don't," sgourakis said. It turns out to be a matter of protein dynamics. "

The researchers found that if the three-dimensional structure of mhc-1 is rigid, the molecular chaperone does not participate in antigen loading. However, if it is flexible in the peptide binding trough, the partner will interact with it and contribute to the antigen loading process. Molecular chaperones can spray antigens with low affinity to the binding trough, so as to ensure that mhc-1 protein only binds high affinity antigens which can be displayed on the cell surface with appropriate conformation, thus activating T cell response. Sgourakis says flexible grooves allow mhc-1 molecules to adapt to a wider range of antigens. (Biovalley Bioon.com )

Source of information: dynamics of critical immune system proteins

Original sources: Andrew C. mcshan, Christine A. Devlin, Sarah A. overall, jihye Park, jugmohit S. toor, Danai moschidi, David Flores Solis, Hannah Choi, sarvind Tripathi, Erik procko, and Nikolaos g. sgourakis. Molecular determinations of champion interactions on MHC-I for following and anti repertoire selection. PNAs, 2019 DOI: 10.1073/pnas.1915562116

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