Function-related regulation of the stability of MHC proteins

Proteins must be stable to accomplish their biological function and to avoi d enzymatic degradation. Constitutive proteolysis, however, is the main sou rce of free amino acids used for de novo protein synthesis. In this paper t he delicate balance of protein stability and degradability is discussed in the context of function of major histocompatibility complex (MHC) encoded p rotein. Classical MHC proteins are single-use peptide transporters that car ry proteolytic degradation products to the cell surface for presenting them to T cells. These proteins fulfill their function as long as they bind the ir dissociable ligand, the peptide. Ligand-free MHC molecules on the cell s urface are practically useless for their primary biological function, but m ay acquire novel activity or become an important source of amino acids when they lose their compact stable structure, which resists proteolytic attack s. We show in this paper that one or more of the stabilization centers resp onsible for the stability of MHC-peptide complexes is composed of residues of both the protein and the peptide, therefore missing in the ligand-free p rotein. This arrangement of stabilization centers provides a simple means o f regulation; it makes the useful form of the protein stable, whereas the u seless form of the same protein is unstable and therefore degradable.