Class I Major Histocompatibility Complex, the Trojan Horse for Secretion of Amyloidogenic β2-Microglobulin

Background: Amyloidogenic D76N (2)m variant escapes the intracellular quality control despite its instability. Results: We show tridimensional structure and stability of D76N (2)m assembled within MHCI compared with the wild type protein. Conclusion: Assembly of D76N (2)m within the MHCI totally masks its misfolding propensity. Significance: The MHCI-mediated stabilization of amyloidogenic D76N (2)m explains the failure of quality control in preventing its secretion. To form extracellular aggregates, amyloidogenic proteins bypass the intracellular quality control, which normally targets unfolded/aggregated polypeptides. Human D76N (2)-microglobulin ((2)m) variant is the prototype of unstable and amyloidogenic protein that forms abundant extracellular fibrillar deposits. Here we focus on the role of the class I major histocompatibility complex (MHCI) in the intracellular stabilization of D76N (2)m. Using biophysical and structural approaches, we show that the MHCI containing D76N (2)m (MHCI76) displays stability, dissociation patterns, and crystal structure comparable with those of the MHCI with wild type (2)m. Conversely, limited proteolysis experiments show a reduced protease susceptibility for D76N (2)m within the MHCI76 as compared with the free variant, suggesting that the MHCI has a chaperone-like activity in preventing D76N (2)m degradation within the cell. Accordingly, D76N (2)m is normally assembled in the MHCI and circulates as free plasma species in a transgenic mouse model.