HMGB1 B-Box Domain Associates Promote Protein–Polyelectrolyte Interactions
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| Title: | HMGB1 B-Box Domain Associates Promote Protein–Polyelectrolyte Interactions |
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| Authors: | Marten Kagelmacher, Marina Pigaleva, Ricardo Zarate, Leïla Bechtella, Kevin Pagel, Beate Koksch, Jens Dernedde, Andreas Herrmann, Thomas Risse |
| Source: | The Journal of Physical Chemistry B. 129:9293-9303 |
| Publisher Information: | American Chemical Society (ACS), 2025. |
| Publication Year: | 2025 |
| Subject Terms: | Heparin, Chemie und zugeordnete Wissenschaften, FOS: Biological sciences, Genetics, Molecules |
| Description: | HMGB1, a nuclear DNA-binding protein, can be secreted by activated immune cells or passively released from damaged cells. In such cases, HMGB1 functions as an alarmin that activates the immune system. Excessive inflammation may lead to pathogenesis, whereas this response can be dampened by polyanion binding, which impedes further receptor recognition. Moreover, HMGB1 is known to form liquid droplets in the cellular environment─a phase separation directly linked to its proper function. While the A-Box domain is believed to be primarily responsible for heparin binding due to its conserved binding site, the association and phase separation behavior of HMGB1 may be mediated by the B-box domain, owing to its extended hydrophobic regions. In this study, we first demonstrated that the B-box protein forms 30 nm large self-associates while maintaining its structure. Next, using molecularly sensitive EPR spectroscopy, we showed that the presence of these protein associates significantly enhances interactions with heparin. Notably, the local conformational changes induced by heparin are similar in both individual protein chains and their self-associated forms. To explain this effect, AlphaFold modeling was employed, revealing that the formation of protein multimers induces charge redistribution, resulting in an extended positively charged region that enhances electrostatic attraction to negatively charged polyanions such as heparin. |
| Document Type: | Article Other literature type |
| Language: | English |
| ISSN: | 1520-5207 1520-6106 |
| DOI: | 10.1021/acs.jpcb.5c02892 |
| DOI: | 10.17169/refubium-48936 |
| Rights: | CC BY |
| Accession Number: | edsair.doi.dedup.....5e2c08aba34c914a28d2ea0cb83b0e35 |
| Database: | OpenAIRE |
Nájsť tento článok vo Web of Science | Abstract: | HMGB1, a nuclear DNA-binding protein, can be secreted by activated immune cells or passively released from damaged cells. In such cases, HMGB1 functions as an alarmin that activates the immune system. Excessive inflammation may lead to pathogenesis, whereas this response can be dampened by polyanion binding, which impedes further receptor recognition. Moreover, HMGB1 is known to form liquid droplets in the cellular environment─a phase separation directly linked to its proper function. While the A-Box domain is believed to be primarily responsible for heparin binding due to its conserved binding site, the association and phase separation behavior of HMGB1 may be mediated by the B-box domain, owing to its extended hydrophobic regions. In this study, we first demonstrated that the B-box protein forms 30 nm large self-associates while maintaining its structure. Next, using molecularly sensitive EPR spectroscopy, we showed that the presence of these protein associates significantly enhances interactions with heparin. Notably, the local conformational changes induced by heparin are similar in both individual protein chains and their self-associated forms. To explain this effect, AlphaFold modeling was employed, revealing that the formation of protein multimers induces charge redistribution, resulting in an extended positively charged region that enhances electrostatic attraction to negatively charged polyanions such as heparin. |
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| ISSN: | 15205207 15206106 |
| DOI: | 10.1021/acs.jpcb.5c02892 |