Calcium Binds to Transthyretin with Low Affinity
The plasma protein transthyretin (TTR), a transporter for thyroid hormones and retinol in plasma and cerebrospinal fluid, is responsible for the second most common type of systemic (ATTR) amyloidosis either in its wild type form or as a result of destabilizing genetic mutations that increase its agg...
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MDPI AG
2022-08-01
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| Series: | Biomolecules |
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| author | Cristina Cantarutti Maria Chiara Mimmi Guglielmo Verona Walter Mandaliti Graham W. Taylor P. Patrizia Mangione Sofia Giorgetti Vittorio Bellotti Alessandra Corazza |
| author_facet | Cristina Cantarutti Maria Chiara Mimmi Guglielmo Verona Walter Mandaliti Graham W. Taylor P. Patrizia Mangione Sofia Giorgetti Vittorio Bellotti Alessandra Corazza |
| author_sort | Cristina Cantarutti |
| collection | DOAJ |
| description | The plasma protein transthyretin (TTR), a transporter for thyroid hormones and retinol in plasma and cerebrospinal fluid, is responsible for the second most common type of systemic (ATTR) amyloidosis either in its wild type form or as a result of destabilizing genetic mutations that increase its aggregation propensity. The association between free calcium ions (Ca<sup>2+</sup>) and TTR is still debated, although recent work seems to suggest that calcium induces structural destabilization of TTR and promotes its aggregation at non-physiological low pH in vitro. We apply high-resolution NMR spectroscopy to investigate calcium binding to TTR showing the formation of labile interactions, which leave the native structure of TTR substantially unaltered. The effect of calcium binding on TTR-enhanced aggregation is also assessed at physiological pH through the mechano-enzymatic mechanism. Our results indicate that, even if the binding is weak, about 7% of TTR is likely to be Ca<sup>2+</sup>-bound in vivo and therefore more aggregation prone as we have shown that this interaction is able to increase the protein susceptibility to the proteolytic cleavage that leads to aggregation at physiological pH. These events, even if involving a minority of circulating TTR, may be relevant for ATTR, a pathology that takes several decades to develop. |
| first_indexed | 2024-03-09T11:50:18Z |
| format | Article |
| id | doaj.art-477b849ef091434591a20259defacbac |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T11:50:18Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-477b849ef091434591a20259defacbac2023-11-30T23:15:49ZengMDPI AGBiomolecules2218-273X2022-08-01128106610.3390/biom12081066Calcium Binds to Transthyretin with Low AffinityCristina Cantarutti0Maria Chiara Mimmi1Guglielmo Verona2Walter Mandaliti3Graham W. Taylor4P. Patrizia Mangione5Sofia Giorgetti6Vittorio Bellotti7Alessandra Corazza8Department of Medicine, University of Udine, 33100 Udine, ItalyDepartment of Molecular Medicine, Institute of Biochemistry, University of Pavia, 27100 Pavia, ItalyWolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London NW3 2PF, UKDepartment of Medicine, University of Udine, 33100 Udine, ItalyWolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London NW3 2PF, UKDepartment of Molecular Medicine, Institute of Biochemistry, University of Pavia, 27100 Pavia, ItalyIstituto Nazionale Biostrutture e Biosistemi, 00136 Rome, ItalyIstituto Nazionale Biostrutture e Biosistemi, 00136 Rome, ItalyDepartment of Medicine, University of Udine, 33100 Udine, ItalyThe plasma protein transthyretin (TTR), a transporter for thyroid hormones and retinol in plasma and cerebrospinal fluid, is responsible for the second most common type of systemic (ATTR) amyloidosis either in its wild type form or as a result of destabilizing genetic mutations that increase its aggregation propensity. The association between free calcium ions (Ca<sup>2+</sup>) and TTR is still debated, although recent work seems to suggest that calcium induces structural destabilization of TTR and promotes its aggregation at non-physiological low pH in vitro. We apply high-resolution NMR spectroscopy to investigate calcium binding to TTR showing the formation of labile interactions, which leave the native structure of TTR substantially unaltered. The effect of calcium binding on TTR-enhanced aggregation is also assessed at physiological pH through the mechano-enzymatic mechanism. Our results indicate that, even if the binding is weak, about 7% of TTR is likely to be Ca<sup>2+</sup>-bound in vivo and therefore more aggregation prone as we have shown that this interaction is able to increase the protein susceptibility to the proteolytic cleavage that leads to aggregation at physiological pH. These events, even if involving a minority of circulating TTR, may be relevant for ATTR, a pathology that takes several decades to develop.https://www.mdpi.com/2218-273X/12/8/1066TTRamyloidosismechano-enzymatic mechanismmicrocalcificationcalcium dysregulation |
| spellingShingle | Cristina Cantarutti Maria Chiara Mimmi Guglielmo Verona Walter Mandaliti Graham W. Taylor P. Patrizia Mangione Sofia Giorgetti Vittorio Bellotti Alessandra Corazza Calcium Binds to Transthyretin with Low Affinity Biomolecules TTR amyloidosis mechano-enzymatic mechanism microcalcification calcium dysregulation |
| title | Calcium Binds to Transthyretin with Low Affinity |
| title_full | Calcium Binds to Transthyretin with Low Affinity |
| title_fullStr | Calcium Binds to Transthyretin with Low Affinity |
| title_full_unstemmed | Calcium Binds to Transthyretin with Low Affinity |
| title_short | Calcium Binds to Transthyretin with Low Affinity |
| title_sort | calcium binds to transthyretin with low affinity |
| topic | TTR amyloidosis mechano-enzymatic mechanism microcalcification calcium dysregulation |
| url | https://www.mdpi.com/2218-273X/12/8/1066 |
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