How Peptide Binding Influences Autoimmunity

Smaller peptides that are not anchored to the MHC molecule could potentially cause autoimmunity by activating self-reactive T-cells.

AsianScientist (Feb. 17, 2015) – For the first time, researchers have successfully observed the 3D dynamic single-molecule internal motions of a peptide bound to the major histocompatibility complex (MHC). The results, published in The Biophysical Journal, sheds light on how the MHC binds and recognizes peptides to activate the immune system.

MHC is an important protein that controls acquired immune response, presenting pathogens that invade the body to immune cells. Some autoimmune antigen peptides are known to bind loosely to MHC molecules. However, how this loose interaction was related to the molecular mechanism of the immune response is unclear.

In the present study, a research group led by Professor Yuji C. Sasaki at the University of Tokyo, and Associate Professor Haruo Kozono at the Tokyo University of Science, has used the SPring-8 BL40XU beamline X-ray machine to discover how MHC binds to pathogen proteins and activates the immune system by observing the internal dynamics of single molecules.

The researchers examined the internal molecular dynamics of mouse MHC bound to a long peptide antigen (14 amino acid bases) and a short peptide antigen (10 amino acid bases). Using diffracted X-ray tracking (DXT) and taking advantage of a phenomenon known as fluorescence anisotropy, the group calculated the dynamics of each single molecule from observation of the movement of the molecular complex. They discovered that when bound to MHC the short peptide antigen is more mobile than the long peptide antigen and takes a different structure.

Furthermore, the research also showed that rotational movement of the complex is particularly active with respect to the axis of the antigen peptide, and that the antigen/MHC complex takes on a new structure which reacts with autoreactive T-cells.

The technique devised and demonstrated by the research group fuses single-molecule monitoring using a quantum beam with computational science. The authors believe that their approach will find many applications, particularly in the field of immunology.

The article can be found at: Kozono et al. (2015) Single-Molecule Motions of MHC Class II Rely on Bound Peptides.

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Source: University of Tokyo.
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