title: Class I major histocompatibility complex, the trojan horse for secretion of amyloidogenic β2-microglobulin.
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.
authors: From the Dipartimento di Bioscienze, Università di Milano, Via Celoria 26, 20133 Milano, Italy.
authors: Levon
authors: L
authors: Halabelian
authors: Stefano
authors: S
authors: Ricagno
authors: Sofia
authors: S
authors: Giorgetti
authors: Carlo
authors: C
authors: Santambrogio
authors: Alberto
authors: A
authors: Barbiroli
authors: Sara
authors: S
authors: Pellegrino
authors: Adnane
authors: A
authors: Achour
authors: Rita
authors: R
authors: Grandori
authors: Loredana
authors: L
authors: Marchese
authors: Sara
authors: S
authors: Raimondi
authors: P Patrizia
authors: PP
authors: Mangione
authors: Gennaro
authors: G
authors: Esposito
authors: Raya
authors: R
authors: Al-Shawi
authors: J Paul
authors: JP
authors: Simons
authors: Ivana
authors: I
authors: Speck
authors: Monica
authors: M
authors: Stoppini
authors: Martino
authors: M
authors: Bolognesi
authors: Vittorio
authors: V
authors: Bellotti
mesh_terms: D019943:Amino Acid Substitution; D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018360:Crystallography, X-Ray; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D001613:beta 2-Microglobulin / Q000235:genetics / Q000378:metabolism*
chemical_list: D000682:Amyloid; D015395:Histocompatibility Antigens Class I; D001613:beta 2-Microglobulin
keywords: Amyloid; Beta2 Microglobulin Amyloidosis; D76N Beta2-Microglobulin Variant; Major Histocompatibility Complex (MHC); Protein Aggregation; Protein Complexes; Protein Structure