Calcium Binds to Transthyretin with Low Affinity.
Calcium Binds to Transthyretin with Low Affinity.
复制标题
钙以低亲和力与甲状腺激素结合。
DOI：
10.3390/biom12081066
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发表时间：
2022-08-02
期刊：
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
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作者：
血浆蛋白转甲状腺素（TTR）是血浆和脑脊液中甲状腺激素和视黄醇的转运体，是第二常见的系统性（ATTR）淀粉样变性的原因，要么是其野生型，要么是不稳定的基因突变增加其聚集倾向的结果。游离钙离子（Ca2+）和TTR之间的关系仍然存在争议，尽管最近的研究似乎表明，钙诱导TTR的结构不稳定，并促进其在体外非生理性低pH下的聚集。我们应用高分辨率核磁共振波谱来研究钙与TTR的结合，显示了不稳定相互作用的形成，这使得TTR的天然结构基本不变。钙结合对trr增强聚集的影响也通过机械-酶机制在生理pH下进行了评估。我们的研究结果表明，即使这种结合很弱，大约7%的TTR可能在体内与Ca2+结合，因此更容易聚集，因为我们已经证明这种相互作用能够增加蛋白质对蛋白水解裂解的敏感性，从而导致生理ph下的聚集。这些事件，即使涉及少数循环TTR，也可能与ATTR有关，这是一种需要几十年才能发展的病理。
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 (Ca2+) 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 Ca2+-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.
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DOI：
10.1074/jbc.ra118.003990
发表时间：
2018-09-14
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Mangione PP;Verona G;Corazza A;Marcoux J;Canetti D;Giorgetti S;Raimondi S;Stoppini M;Esposito M;Relini A;Canale C;Valli M;Marchese L;Faravelli G;Obici L;Hawkins PN;Taylor GW;Gillmore JD;Pepys MB;Bellotti V
通讯作者：
Bellotti V
影响因子：
4.6
作者：
Ciccone L;Fruchart-Gaillard C;Mourier G;Savko M;Nencetti S;Orlandini E;Servent D;Stura EA;Shepard W
通讯作者：
Shepard W
影响因子：
--
作者：
Rodrigues, Joao P G L M;Teixeira, Joao M C;Bonvin, Alexandre M J J
通讯作者：
Bonvin, Alexandre M J J
DOI：
10.1016/j.colsurfa.2017.05.019
发表时间：
2017-08-20
影响因子：
5.2
作者：
Khiabani, N. P.;Bahramian, A.;Ejtehadi, M. R.
通讯作者：
Ejtehadi, M. R.
DOI：
10.1107/s090744491104491x
发表时间：
2011-12-01
影响因子：
2.2
作者：
Castro-Rodrigues, Artur F.;Gales, Luis;Damas, Ana M.
通讯作者：
Damas, Ana M.