National Center for
4L3C: Structure Of Hla-a2 In Complex With D76n B2m Mutant And Ny-eso1 Double Mutant
Class I Major Histocompatibility Complex, the Trojan Horse for Secretion of Amyloidogenic beta2-Microglobulin
J. Biol. Chem. (2014) 289 p.3318-3327
To form extracellular aggregates, amyloidogenic proteins bypass the intracellular quality control, which normally targets unfolded/aggregated polypeptides. Human D76N beta2-microglobulin (beta2m) 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 beta2m. Using biophysical and structural approaches, we show that the MHCI containing D76N beta2m (MHCI76) displays stability, dissociation patterns, and crystal structure comparable with those of the MHCI with wild type beta2m. Conversely, limited proteolysis experiments show a reduced protease susceptibility for D76N beta2m within the MHCI76 as compared with the free variant, suggesting that the MHCI has a chaperone-like activity in preventing D76N beta2m degradation within the cell. Accordingly, D76N beta2m is normally assembled in the MHCI and circulates as free plasma species in a transgenic mouse model.