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

    Fingerprint

    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

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    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.

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