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

• Published in: The Journal of biological chemistry 2014-02, Vol.289 (6), p.3318-3327
• Main Authors: Halabelian, Levon, Ricagno, Stefano, Giorgetti, Sofia, Santambrogio, Carlo, Barbiroli, Alberto, Pellegrino, Sara, Achour, Adnane, Grandori, Rita, Marchese, Loredana, Raimondi, Sara, Mangione, P. Patrizia, Esposito, Gennaro, Al-Shawi, Raya, Simons, J. Paul, Speck, Ivana, Stoppini, Monica, Bolognesi, Martino, Bellotti, Vittorio
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution; Amyloid; Amyloid - genetics; Amyloid - metabolism; Animals; beta 2-Microglobulin - genetics; beta 2-Microglobulin - metabolism; Beta2 Microglobulin Amyloidosis; Crystallography, X-Ray; D76N Beta2-Microglobulin Variant; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - metabolism; Humans; Major Histocompatibility Complex (MHC); Mice; Mice, Transgenic; Mutation, Missense; Protein Aggregation; Protein Complexes; Protein Structure; Protein Structure and Folding
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.524157

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 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 β2m. Using biophysical and structural approaches, we show that the MHCI containing D76N β2m (MHCI76) displays stability, dissociation patterns, and crystal structure comparable with those of the MHCI with wild type β2m. Conversely, limited proteolysis experiments show a reduced protease susceptibility for D76N β2m within the MHCI76 as compared with the free variant, suggesting that the MHCI has a chaperone-like activity in preventing D76N β2m degradation within the cell. Accordingly, D76N β2m is normally assembled in the MHCI and circulates as free plasma species in a transgenic mouse model. Background: Amyloidogenic D76N β2m variant escapes the intracellular quality control despite its instability. Results: We show tridimensional structure and stability of D76N β2m assembled within MHCI compared with the wild type protein. Conclusion: Assembly of D76N β2m within the MHCI totally masks its misfolding propensity. Significance: The MHCI-mediated stabilization of amyloidogenic D76N β2m explains the failure of quality control in preventing its secretion.