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 β2mexplains 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 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, D76Nβ2mis normally assembled in theMHCIand circulates as free plasma species in a transgenic mouse model.© 2014 by The American Society for Biochemistry and Molecular Biology, Inc

Halabelian, L., Ricagno, S., Giorgetti, S., Santambrogio, C., Barbiroli, A., Pellegrino, S., et al. (2014). Class I major histocompatibility complex, the Trojan Horse for secretion of Amyloidogenic β2-Microglobulin. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 289(6), 3318-3327 [10.1074/jbc.M113.524157].

Class I major histocompatibility complex, the Trojan Horse for secretion of Amyloidogenic β2-Microglobulin

SANTAMBROGIO, CARLO;GRANDORI, RITA;
2014

Abstract

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 β2mexplains 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 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, D76Nβ2mis normally assembled in theMHCIand circulates as free plasma species in a transgenic mouse model.© 2014 by The American Society for Biochemistry and Molecular Biology, Inc
Articolo in rivista - Articolo scientifico
Amyloid; Beta2 Microglobulin Amyloidosis; D76N Beta2-Microglobulin Variant; Major Histocompatibility Complex (MHC); Protein Aggregation; Protein Complexes; Protein Structure; Amino Acid Substitution; Amyloid; Animals; Crystallography, X-Ray; Histocompatibility Antigens Class I; Humans; Mice; Mice, Transgenic; beta 2-Microglobulin; Mutation, Missense; Biochemistry; Cell Biology; Molecular Biology
English
2014
289
6
3318
3327
none
Halabelian, L., Ricagno, S., Giorgetti, S., Santambrogio, C., Barbiroli, A., Pellegrino, S., et al. (2014). Class I major histocompatibility complex, the Trojan Horse for secretion of Amyloidogenic β2-Microglobulin. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 289(6), 3318-3327 [10.1074/jbc.M113.524157].
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/95744
Citazioni
  • Scopus 21
  • ???jsp.display-item.citation.isi??? 21
Social impact