Department of Chemistry, Oxford University, United Kingdom.
ACS Chem Biol. 2010 Dec 17;5(12):1137-46. doi: 10.1021/cb100144v. Epub 2010 Oct 7.
Transthyretin (TTR) is a plasma hormone carrier protein associated with hereditary and senile forms of systemic amyloid disease, wherein slow tetramer disassembly is thought to be an obligatory step. Plasma transport of retinol is carried out exclusively by the retinol-binding protein (RBP), through complexation with transthyretin. Using mass spectrometry to examine the subunit exchange dynamics, we find that retinol stabilizes the quaternary structure of transthyretin, through its interactions with RBP, reducing the rate of transthyretin disassembly ∼17-fold compared to apoTTR. In the absence of retinol but in the presence of RBP, transthyretin is only marginally stabilized with the rate of disassembly reduced ∼two-fold with respect to apoTTR. Surprisingly, we found two retinoids that stabilize transthyretin directly, in the absence of RBP, whereas retinol itself requires RBP in order to stabilize transthyretin. Our results demonstrate new roles for RBP and retinoids as stabilizers of transthyretin.
转甲状腺素蛋白（TTR）是一种与遗传性和老年性系统性淀粉样变性疾病相关的血浆激素载体蛋白，其中缓慢的四聚体解体被认为是一个必需的步骤。视黄醇的血浆转运完全由视黄醇结合蛋白（RBP）通过与转甲状腺素蛋白的复合物来完成。通过质谱分析研究亚基交换动力学，我们发现视黄醇通过与 RBP 的相互作用稳定转甲状腺素蛋白的四级结构，使转甲状腺素蛋白的解体速度比apoTTR 降低约 17 倍。在没有视黄醇但存在 RBP 的情况下，转甲状腺素蛋白仅得到轻微稳定，其解体速度比 apoTTR 降低约 2 倍。令人惊讶的是，我们发现了两种视黄醇衍生物，它们在没有 RBP 的情况下直接稳定转甲状腺素蛋白，而视黄醇本身需要 RBP 才能稳定转甲状腺素蛋白。我们的结果表明，RBP 和视黄醇衍生物在稳定转甲状腺素蛋白方面具有新的作用。
