4L3C

Structure of HLA-A2 in complex with D76N b2m mutant and NY-ESO1 double mutant

Summary for 4L3C

• Entry DOI: 10.2210/pdb4l3c/pdb
• Related: 4L29
• Descriptor: HLA class I histocompatibility antigen, A-2 alpha chain, Beta-2-microglobulin, NY-ESO1 double mutant (1Y, 9V), ... (6 entities in total)
• Functional Keywords: mhc, beta-2 microglobulin, hla_a0201, ny-eso1, d76n variant, immunglobulin, beta sandwitch, immune system, amyloid aggregation
• Biological source: Homo sapiens (human); More
• Cellular location: Membrane; Single-pass type I membrane protein: P01892; Secreted: P61769
• Total number of polymer chains: 42
• Total formula weight: 633134.76

Authors

Halabelian, L.,Giorgetti, S.,Bellotti, V.,Bolognesi, M.,Ricagno, S. (deposition date: 2013-06-05, release date: 2013-12-25, Last modification date: 2024-10-30)

Primary citation

Halabelian, L.,Ricagno, S.,Giorgetti, S.,Santambrogio, C.,Barbiroli, A.,Pellegrino, S.,Achour, A.,Grandori, R.,Marchese, L.,Raimondi, S.,Mangione, P.P.,Esposito, G.,Al-Shawi, R.,Simons, J.P.,Speck, I.,Stoppini, M.,Bolognesi, M.,Bellotti, V.
Class I Major Histocompatibility Complex, the Trojan Horse for Secretion of Amyloidogenic beta 2-Microglobulin.
J.Biol.Chem., 289:3318-3327, 2014

PubMed Abstract: 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.

PubMed: 24338476
DOI: 10.1074/jbc.M113.524157

Experimental method

X-RAY DIFFRACTION (2.64 Å)