ENTROPY-DRIVEN PROTEIN SELF-AGGREGATION AS THE BASIS FOR SELF/NOT-SELF DISCRIMINATION IN THE CROWDED CYTOSOL

Abstract

Cytotoxic T cells recognize cell surface complexes of MHC class I proteins with peptides derived from proteins synthesized within the recognized cell. A mechanism permitting some intracellular discrimination between self proteins and not-self proteins (encoded by a foreign species) would allow the preferential loading of MHC proteins with peptides derived from not-self proteins. This would decrease competition with peptides derived from self proteins and decrease gaps in the T cell repertoire. A possible mechanism has been derived from studies of the specificity of self-aggregation of erythrocytes and of virus coat protein. It is postulated that genes whose products occupy a common cytosol have co-evolved such that product concentrations are fine-tuned to a maximum consistent with avoiding self-aggregation. Cytosolic proteins collectively generate a pressure tending to drive protein molecules into self-aggregates. Each individual protein species both contributes to, and is influenced by, this pressure. The aggregation involves a liberation of bound water and an increase in entropy. The concentrations of proteins encoded by viral genes (not-self) readily exceed the solubility limits imposed by the crowded host cytosol. This leads to their preferential degradation to peptides which associate with MHC proteins. The intracellular and extracellular self/not-self discrimination systems complement each other to ensure that there is no immunological reaction against normal self tissue components.