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.
I: Free Radical Biology and Medicine, Bind 187, 2022, s. 59-71.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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