[2] It does this by assisting in peptide loading of major histocompatibility complex (MHC) class II membrane-bound proteins.
[4] HLA-DM is a molecular chaperone[5] that works in lysosomes and endosomes in cells of the immune system.
[7] HLA-DM protects the MHC class II molecules from breaking down, and regulates which proteins or peptides bind to them as well.
Without it, T cells leaving their site of production and entering the circulatory vessels of the body will not be activated against a danger.
[15] In order to ensure that no false peptides bind to an MHC class II molecule, the peptide-binding groove is occupied by a protein called CLIP.
Through expulsion of CLIP at the proper time, HLA-DM ensures that the correct antigen can bind to MHC molecules and prevent either from degrading.
This process occurs in endosomes once they have left the ER containing MHC and HLA-DM that have fused with antigen-containing lysosomes.
Along the membrane of an endosome at the optimal acidity (pH=5.0), HLA-DM loads 3 to 12 peptides onto different MHC molecules per minute.
Much of this pathway is still being researched, but it is known that HLA-DM can load exogenous peptides onto MHC class II molecules when they are being expressed on cell surfaces.
[14] Before encountering an antigen, DO acts as a chaperone of DM to stabilize it against denaturation and direct it into lysosomes.
Research in crystallography has resulted in advanced knowledge on HLA-DM structure, and how it binds to its substrates (HLA-DO and MHC class II molecules).
[9] The structure and sequence of HLA-DM proteins is very similar to other MHC class II molecules,[11] all of which consist of a heterodimer composed of an alpha and beta chain.
However, HLA-DM differs in that it is nonclassical (meaning it lacks a transport signal N-terminus), and does not have the capability to bind peptides.
This is due to lack of a deep peptide binding groove – instead, it contains a shallow, negatively charged indent with two disulfide bonds.
Intracellularly, HLA-DM is translated in the endoplasmic reticulum, then transported to endosomal MHC class II compartments (MIICs).
[14] Within the body, highest levels of HLA-DM expression is found in lymph nodes, the spleen, and bone marrow.