Oxidant-mediated modification and cross-linking of beta-2-microglobulin

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Oxidant-mediated modification and cross-linking of beta-2-microglobulin. / Jiang, Shuwen; Fuentes-Lemus, Eduardo; Davies, Michael J.

In: Free Radical Biology and Medicine, Vol. 187, 2022, p. 59-71.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Jiang, S, Fuentes-Lemus, E & Davies, MJ 2022, 'Oxidant-mediated modification and cross-linking of beta-2-microglobulin', Free Radical Biology and Medicine, vol. 187, pp. 59-71. https://doi.org/10.1016/j.freeradbiomed.2022.05.012

APA

Jiang, S., Fuentes-Lemus, E., & Davies, M. J. (2022). Oxidant-mediated modification and cross-linking of beta-2-microglobulin. Free Radical Biology and Medicine, 187, 59-71. https://doi.org/10.1016/j.freeradbiomed.2022.05.012

Vancouver

Jiang S, Fuentes-Lemus E, Davies MJ. Oxidant-mediated modification and cross-linking of beta-2-microglobulin. Free Radical Biology and Medicine. 2022;187:59-71. https://doi.org/10.1016/j.freeradbiomed.2022.05.012

Author

Jiang, Shuwen ; Fuentes-Lemus, Eduardo ; Davies, Michael J. / Oxidant-mediated modification and cross-linking of beta-2-microglobulin. In: Free Radical Biology and Medicine. 2022 ; Vol. 187. pp. 59-71.

Bibtex

@article{fd8761a4ca374bb7aee53128fb9ccdac,
title = "Oxidant-mediated modification and cross-linking of beta-2-microglobulin",
abstract = "Beta-2-microglobulin (B2M) is synthesized by all nucleated cells and forms part of the major histocompatibility complex (MHC) class-1 present on cell surfaces, which presents peptide fragments to cytotoxic CD8+ T-lymphocytes, or by association with CD1, antigenic lipids to natural killer T-cells. Knockout of B2M results in loss of these functions and severe combined immunodeficiency. Plasma levels of this protein are low in healthy serum, but are elevated up to 50-fold in some pathologies including chronic kidney disease and multiple myeloma, where it has both diagnostic and prognostic value. High levels of the protein are associated with amyloid formation, with such deposits containing significant levels of modified or truncated protein. In the current study we examine the chemical and structural changes induced of B2M generated by both inflammatory oxidants (HOCl and ONOOH), and photo-oxidation (1O2) which is linked with immunosuppression. Oxidation results in oligomer formation, with this occurring most readily with HOCl and 1O2, and a loss of native protein conformation. LC-MS analysis provided evidence for nitrated (from ONOOH), chlorinated (from HOCl) and oxidized residues (all oxidants) with damage detected at Tyr, Trp, and Met residues, together with cleavage of the disulfide (cystine) bond. An intermolecular di-tyrosine crosslink is also formed between Tyr10 and Tyr63. The pattern of these modifications is oxidant specific, with ONOOH inducing a greater range of modifications than HOCl. Comparison of the sites of modification with regions identified as amyloidogenic indicate significant co-localization, consistent with the hypothesis that oxidation may contribute, and predispose B2M, to amyloid formation.",
keywords = "Beta-2-microglobulin, Hypochlorous acid, Peroxynitrite, Protein cross-linking, Protein modification, Singlet oxygen",
author = "Shuwen Jiang and Eduardo Fuentes-Lemus and Davies, {Michael J.}",
note = "Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
doi = "10.1016/j.freeradbiomed.2022.05.012",
language = "English",
volume = "187",
pages = "59--71",
journal = "Free Radical Biology & Medicine",
issn = "0891-5849",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - Oxidant-mediated modification and cross-linking of beta-2-microglobulin

AU - Jiang, Shuwen

AU - Fuentes-Lemus, Eduardo

AU - Davies, Michael J.

N1 - Publisher Copyright: © 2022 The Authors

PY - 2022

Y1 - 2022

N2 - Beta-2-microglobulin (B2M) is synthesized by all nucleated cells and forms part of the major histocompatibility complex (MHC) class-1 present on cell surfaces, which presents peptide fragments to cytotoxic CD8+ T-lymphocytes, or by association with CD1, antigenic lipids to natural killer T-cells. Knockout of B2M results in loss of these functions and severe combined immunodeficiency. Plasma levels of this protein are low in healthy serum, but are elevated up to 50-fold in some pathologies including chronic kidney disease and multiple myeloma, where it has both diagnostic and prognostic value. High levels of the protein are associated with amyloid formation, with such deposits containing significant levels of modified or truncated protein. In the current study we examine the chemical and structural changes induced of B2M generated by both inflammatory oxidants (HOCl and ONOOH), and photo-oxidation (1O2) which is linked with immunosuppression. Oxidation results in oligomer formation, with this occurring most readily with HOCl and 1O2, and a loss of native protein conformation. LC-MS analysis provided evidence for nitrated (from ONOOH), chlorinated (from HOCl) and oxidized residues (all oxidants) with damage detected at Tyr, Trp, and Met residues, together with cleavage of the disulfide (cystine) bond. An intermolecular di-tyrosine crosslink is also formed between Tyr10 and Tyr63. The pattern of these modifications is oxidant specific, with ONOOH inducing a greater range of modifications than HOCl. Comparison of the sites of modification with regions identified as amyloidogenic indicate significant co-localization, consistent with the hypothesis that oxidation may contribute, and predispose B2M, to amyloid formation.

AB - Beta-2-microglobulin (B2M) is synthesized by all nucleated cells and forms part of the major histocompatibility complex (MHC) class-1 present on cell surfaces, which presents peptide fragments to cytotoxic CD8+ T-lymphocytes, or by association with CD1, antigenic lipids to natural killer T-cells. Knockout of B2M results in loss of these functions and severe combined immunodeficiency. Plasma levels of this protein are low in healthy serum, but are elevated up to 50-fold in some pathologies including chronic kidney disease and multiple myeloma, where it has both diagnostic and prognostic value. High levels of the protein are associated with amyloid formation, with such deposits containing significant levels of modified or truncated protein. In the current study we examine the chemical and structural changes induced of B2M generated by both inflammatory oxidants (HOCl and ONOOH), and photo-oxidation (1O2) which is linked with immunosuppression. Oxidation results in oligomer formation, with this occurring most readily with HOCl and 1O2, and a loss of native protein conformation. LC-MS analysis provided evidence for nitrated (from ONOOH), chlorinated (from HOCl) and oxidized residues (all oxidants) with damage detected at Tyr, Trp, and Met residues, together with cleavage of the disulfide (cystine) bond. An intermolecular di-tyrosine crosslink is also formed between Tyr10 and Tyr63. The pattern of these modifications is oxidant specific, with ONOOH inducing a greater range of modifications than HOCl. Comparison of the sites of modification with regions identified as amyloidogenic indicate significant co-localization, consistent with the hypothesis that oxidation may contribute, and predispose B2M, to amyloid formation.

KW - Beta-2-microglobulin

KW - Hypochlorous acid

KW - Peroxynitrite

KW - Protein cross-linking

KW - Protein modification

KW - Singlet oxygen

UR - http://www.scopus.com/inward/record.url?scp=85130791379&partnerID=8YFLogxK

U2 - 10.1016/j.freeradbiomed.2022.05.012

DO - 10.1016/j.freeradbiomed.2022.05.012

M3 - Journal article

C2 - 35609861

AN - SCOPUS:85130791379

VL - 187

SP - 59

EP - 71

JO - Free Radical Biology & Medicine

JF - Free Radical Biology & Medicine

SN - 0891-5849

ER -

ID: 311120250