Chaperones rescue the energetic landscape of mutant CFTR at single molecule and in cell.
Chaperones rescue the energetic landscape of mutant CFTR at single molecule and in cell.
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伴侣在单分子和细胞中拯救了突变CFTR的能量景观。
DOI：
10.1038/s41467-017-00444-4
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发表时间：
2017-08-30
影响因子：
16.6
通讯作者：
Lukacs GL
中科院分区：
文献类型：
--
作者：
Bagdany M;Veit G;Fukuda R;Avramescu RG;Okiyoneda T;Baaklini I;Singh J;Sovak G;Xu H;Apaja PM;Sattin S;Beitel LK;Roldan A;Colombo G;Balch W;Young JC;Lukacs GL
分子伴侣在细胞蛋白质组的折叠和降解中起关键作用，但它们对与疾病相关的近天然膜蛋白构象动力学的影响尚不清楚。在这里，我们报道了伴侣活性对温度敏感型突变型囊性纤维化通道(∆F508-cftr)在质膜上和重组为磷脂双层后功能构象的影响。37 °C下热诱导的展开和伴随的∆F508-cftr的功能失活部分地被体内质膜和内质网后隔室的Hsc70和Hsp90伴侣/共伴侣的构造活性抑制，在体外的单分子水平上，表明突变的能量学向野生型的动力学和热力学重塑。因此，分子伴侣可以通过重塑其最后折叠的构象能量学来帮助维持∆F508-cftr的功能，这一机制在调节亚稳定的ABC转运蛋白和其他健康和疾病中的质膜蛋白活性方面具有重要意义。囊性纤维化跨膜电导调节因子(CFTR)中的F508缺失(F508del)是引起囊性纤维化最常见的突变。在这里，作者表明，胞质伴侣通过动力学和热力学重塑门控能量使F508del通道构象向自然折叠转变为野生型CTFR。
Molecular chaperones are pivotal in folding and degradation of the cellular proteome but their impact on the conformational dynamics of near-native membrane proteins with disease relevance remains unknown. Here we report the effect of chaperone activity on the functional conformation of the temperature-sensitive mutant cystic fibrosis channel (∆F508-CFTR) at the plasma membrane and after reconstitution into phospholipid bilayer. Thermally induced unfolding at 37 °C and concomitant functional inactivation of ∆F508-CFTR are partially suppressed by constitutive activity of Hsc70 and Hsp90 chaperone/co-chaperone at the plasma membrane and post-endoplasmic reticulum compartments in vivo, and at single-molecule level in vitro, indicated by kinetic and thermodynamic remodeling of the mutant gating energetics toward its wild-type counterpart. Thus, molecular chaperones can contribute to functional maintenance of ∆F508-CFTR by reshaping the conformational energetics of its final fold, a mechanism with implication in the regulation of metastable ABC transporters and other plasma membrane proteins activity in health and diseases. The F508 deletion (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) is the most common CF causing mutation. Here the authors show that cytosolic chaperones shift the F508del channel conformation to the native fold by kinetic and thermodynamic remodelling of the gating energetics towards that of wild-type CTFR.
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影响因子：
14.8
作者：
Hebert, Daniel N.;Lamriben, Lydia;Powers, Evan T.;Kelly, Jeffery W.
通讯作者：
Kelly, Jeffery W.
影响因子：
3.3
作者：
Cho, Samuel S.;Reddy, Govardhan;Thirumalai, D.
通讯作者：
Thirumalai, D.
影响因子：
3.5
作者：
Aleksandrov, AA;Riordan, JR
通讯作者：
Riordan, JR
DOI：
10.1038/nrg3849
发表时间：
2015-01
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.5
作者：
Frederick KK;Michaelis VK;Corzilius B;Ong TC;Jacavone AC;Griffin RG;Lindquist S
通讯作者：
Lindquist S