articolo postato il: 2013-12-26 19:40:31
Class I Major Histocompatibility Complex, the Trojan Horse for Secretion of Amyloidogenic b2-Microglobulin
To form extracellular aggregates, amyloidogenic proteins bypass the intracellular quality control which normally targets unfolded/aggregated polypeptides. Human D76N β2-microglobulin (β2m) variant is the prototype of unstable and amyloidogenic protein which forms abundant extracellular fibrillar deposits. Here we focus on the role of the Class I Major Histocompatibility Complex (MHC) in the intracellular stabilization of D76N β2m. Using biophysical and structural approaches we show that the MHC containing D76N β2m (MHC76) displays stability, dissociation patterns and crystal structure comparable to those of the MHC with wild type β2m. Conversely, limited proteolysis experiments show a reduced protease susceptibility for D76N β2m within the MHC76 compared to the free variant, suggesting that the MHC has a chaperone-like activity in preventing D76N β2m degradation within the cell. Accordingly, D76N β2m is normally assembled in the MHC and circulates as free plasma species in a transgenic mouse model.