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

Levon Halabelian, Stefano Ricagno, Sofia Giorgetti, Carlo Santambrogio, Alberto Barbiroli, Sara Pellegrino, Adnane Achour, Rita Grandori, Loredana Marchese, Sara Raimondi, P. Patrizia Mangione, Gennaro Esposito, Raya Al-Shawi, J. Paul Simons, Ivana Speck, Monica Stoppini, Martino Bolognesi, Vittorio Bellotti

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)3318-3327
Number of pages10
JournalJournal of Biological Chemistry
Volume289
Issue number6
DOIs
StatePublished - Feb 7 2014

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Major Histocompatibility Complex
Quality control
Amyloidogenic Proteins
Stabilization
Proteolysis
Quality Control
Masks
Peptide Hydrolases
Deposits
Crystal structure
Plasmas
Degradation
Peptides
Proteins
Transgenic Mice
Experiments

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Halabelian, L., Ricagno, S., Giorgetti, S., Santambrogio, C., Barbiroli, A., Pellegrino, S., ... Bellotti, V. (2014). Class I major histocompatibility complex, the Trojan Horse for secretion of Amyloidogenic β2-Microglobulin. Journal of Biological Chemistry, 289(6), 3318-3327. https://doi.org/10.1074/jbc.M113.524157

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

In: Journal of Biological Chemistry, Vol. 289, No. 6, 07.02.2014, p. 3318-3327.

Research output: Contribution to journalArticle

Halabelian, L, Ricagno, S, Giorgetti, S, Santambrogio, C, Barbiroli, A, Pellegrino, S, Achour, A, Grandori, R, Marchese, L, Raimondi, S, Mangione, PP, Esposito, G, Al-Shawi, R, Simons, JP, Speck, I, Stoppini, M, Bolognesi, M & Bellotti, V 2014, 'Class I major histocompatibility complex, the Trojan Horse for secretion of Amyloidogenic β2-Microglobulin', Journal of Biological Chemistry, vol. 289, no. 6, pp. 3318-3327. https://doi.org/10.1074/jbc.M113.524157
Halabelian L, Ricagno S, Giorgetti S, Santambrogio C, Barbiroli A, Pellegrino S et al. Class I major histocompatibility complex, the Trojan Horse for secretion of Amyloidogenic β2-Microglobulin. Journal of Biological Chemistry. 2014 Feb 7;289(6):3318-3327. https://doi.org/10.1074/jbc.M113.524157
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. / Class I major histocompatibility complex, the Trojan Horse for secretion of Amyloidogenic β2-Microglobulin. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 6. pp. 3318-3327.
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T1 - Class I major histocompatibility complex, the Trojan Horse for secretion of Amyloidogenic β2-Microglobulin

AU - Halabelian, Levon

AU - Ricagno, Stefano

AU - Giorgetti, Sofia

AU - Santambrogio, Carlo

AU - Barbiroli, Alberto

AU - Pellegrino, Sara

AU - Achour, Adnane

AU - Grandori, Rita

AU - Marchese, Loredana

AU - Raimondi, Sara

AU - Mangione, P. Patrizia

AU - Esposito, Gennaro

AU - Al-Shawi, Raya

AU - Simons, J. Paul

AU - Speck, Ivana

AU - Stoppini, Monica

AU - Bolognesi, Martino

AU - Bellotti, Vittorio

PY - 2014/2/7

Y1 - 2014/2/7

N2 - 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.

AB - 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.

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