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The residues 4 to 6 at the N-terminus in particular modulate fibril propagation of β (2)-microglobulin : N-terminal modulates β2M fibril propagation
The ΔN6 truncation is the main posttranslational modification of β (2)-microglobulin (β (2)M) found in dialysis-related amyloid. Investigation of the interaction of wild-type (WT) β (2)M with N-terminally truncated variants is therefore of medical relevance. However, it is unclear which residues amo...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9909321/ https://www.ncbi.nlm.nih.gov/pubmed/35130623 http://dx.doi.org/10.3724/abbs.2021017 |
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author | Dang, Haibin Chen, Zhixian Chen, Wang Luo, Xudong Liu, Pan Wang, Liqiang Chen, Jie Tang, Xuhai Wang, Zhengzhi Liang, Yi |
author_facet | Dang, Haibin Chen, Zhixian Chen, Wang Luo, Xudong Liu, Pan Wang, Liqiang Chen, Jie Tang, Xuhai Wang, Zhengzhi Liang, Yi |
author_sort | Dang, Haibin |
collection | PubMed |
description | The ΔN6 truncation is the main posttranslational modification of β (2)-microglobulin (β (2)M) found in dialysis-related amyloid. Investigation of the interaction of wild-type (WT) β (2)M with N-terminally truncated variants is therefore of medical relevance. However, it is unclear which residues among the six residues at the N-terminus are crucial to the interactions and the modulation of amyloid fibril propagation of β (2)M. We herein analyzed homo- and heterotypic seeding of amyloid fibrils of WT human β (2)M and its N-terminally-truncated variants ΔN1 to ΔN6, lacking up to six residues at the N-terminus. At acidic pH 2.5, we produced amyloid fibrils in vitro from recombinant, WT β (2)M and its six truncated variants, and found that ΔN6 β (2)M fibrils exhibit a significantly lower conformational stability than WT β (2)M fibrils. Importantly, under more physiological conditions (pH 6.2), we assembled amyloid fibrils in vitro only from recombinant, ΔN4, ΔN5, and ΔN6 β (2)M but not from WT β (2)M and its three truncated variants ΔN1 to ΔN3. Notably, the removal of the six, five or four residues at the N-terminus leads to enhanced fibril formation, and homo- and heterotypic seeding of ΔN6 fibrils strongly promotes amyloid fibril formation of WT β (2)M and its six truncated variants, including at more physiological pH 6.2. Collectively, these results demonstrated that the residues 4 to 6 at the N-terminus particularly modulate amyloid fibril propagation of β (2)M and the interactions of WT β (2)M with N-terminally truncated variants, potentially indicating the direct relevance to the involvement of the protein’s aggregation in dialysis-related amyloidosis. |
format | Online Article Text |
id | pubmed-9909321 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-99093212023-02-10 The residues 4 to 6 at the N-terminus in particular modulate fibril propagation of β (2)-microglobulin : N-terminal modulates β2M fibril propagation Dang, Haibin Chen, Zhixian Chen, Wang Luo, Xudong Liu, Pan Wang, Liqiang Chen, Jie Tang, Xuhai Wang, Zhengzhi Liang, Yi Acta Biochim Biophys Sin (Shanghai) Research Article The ΔN6 truncation is the main posttranslational modification of β (2)-microglobulin (β (2)M) found in dialysis-related amyloid. Investigation of the interaction of wild-type (WT) β (2)M with N-terminally truncated variants is therefore of medical relevance. However, it is unclear which residues among the six residues at the N-terminus are crucial to the interactions and the modulation of amyloid fibril propagation of β (2)M. We herein analyzed homo- and heterotypic seeding of amyloid fibrils of WT human β (2)M and its N-terminally-truncated variants ΔN1 to ΔN6, lacking up to six residues at the N-terminus. At acidic pH 2.5, we produced amyloid fibrils in vitro from recombinant, WT β (2)M and its six truncated variants, and found that ΔN6 β (2)M fibrils exhibit a significantly lower conformational stability than WT β (2)M fibrils. Importantly, under more physiological conditions (pH 6.2), we assembled amyloid fibrils in vitro only from recombinant, ΔN4, ΔN5, and ΔN6 β (2)M but not from WT β (2)M and its three truncated variants ΔN1 to ΔN3. Notably, the removal of the six, five or four residues at the N-terminus leads to enhanced fibril formation, and homo- and heterotypic seeding of ΔN6 fibrils strongly promotes amyloid fibril formation of WT β (2)M and its six truncated variants, including at more physiological pH 6.2. Collectively, these results demonstrated that the residues 4 to 6 at the N-terminus particularly modulate amyloid fibril propagation of β (2)M and the interactions of WT β (2)M with N-terminally truncated variants, potentially indicating the direct relevance to the involvement of the protein’s aggregation in dialysis-related amyloidosis. Oxford University Press 2021-12-23 /pmc/articles/PMC9909321/ /pubmed/35130623 http://dx.doi.org/10.3724/abbs.2021017 Text en © The Author(s) 2021. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Article Dang, Haibin Chen, Zhixian Chen, Wang Luo, Xudong Liu, Pan Wang, Liqiang Chen, Jie Tang, Xuhai Wang, Zhengzhi Liang, Yi The residues 4 to 6 at the N-terminus in particular modulate fibril propagation of β (2)-microglobulin : N-terminal modulates β2M fibril propagation |
title | The residues 4 to 6 at the N-terminus in particular modulate fibril propagation of β
(2)-microglobulin
: N-terminal modulates β2M fibril propagation |
title_full | The residues 4 to 6 at the N-terminus in particular modulate fibril propagation of β
(2)-microglobulin
: N-terminal modulates β2M fibril propagation |
title_fullStr | The residues 4 to 6 at the N-terminus in particular modulate fibril propagation of β
(2)-microglobulin
: N-terminal modulates β2M fibril propagation |
title_full_unstemmed | The residues 4 to 6 at the N-terminus in particular modulate fibril propagation of β
(2)-microglobulin
: N-terminal modulates β2M fibril propagation |
title_short | The residues 4 to 6 at the N-terminus in particular modulate fibril propagation of β
(2)-microglobulin
: N-terminal modulates β2M fibril propagation |
title_sort | residues 4 to 6 at the n-terminus in particular modulate fibril propagation of β
(2)-microglobulin
: n-terminal modulates β2m fibril propagation |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9909321/ https://www.ncbi.nlm.nih.gov/pubmed/35130623 http://dx.doi.org/10.3724/abbs.2021017 |
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