Packing of apolar side chains enables accurate design of highly stable membrane proteins
Packing of apolar side chains enables accurate design of highly stable membrane proteins
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DOI：
10.1126/science.aav7541
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发表时间：
2019-03-29
期刊：
影响因子：
56.9
通讯作者：
DeGrado, William F.
中科院分区：
文献类型：
--
作者：
Mravic, Marco;Thomaston, Jessica L.;DeGrado, William F.
稳定膜蛋白结构的特征仍然知之甚少。极性相互作用贡献不大，疏水效应对膜中非极性侧链的能量学贡献不大。空间包装的破坏可以使膜蛋白的天然折叠不稳定，但单独包装足以驱动脂质折叠吗？如果是这样的话，那么膜蛋白稳定的这一特点应该很容易设计和结构特征，但这还没有实现。通过模拟天然蛋白受磷蛋白和重新设计的变体，我们定义了一个空间包装代码的组装。使用该密码子设计的合成膜蛋白完全由非极性侧链稳定，符合预期的折叠。尽管高度稳定，但它们折叠所需的空间互补性却令人惊讶地严格。结构信息学表明，设计的包装基序在蛋白质组中反复出现，强调了精确的非极性包装在膜蛋白折叠，稳定和进化中的突出作用。
The features that stabilize the structures of membrane proteins remain poorly understood. Polar interactions contribute modestly, and the hydrophobic effect contributes little to the energetics of apolar side-chain packing in membranes. Disruption of steric packing can destabilize the native folds of membrane proteins, but is packing alone sufficient to drive folding in lipids? If so, then membrane proteins stabilized by this feature should be readily designed and structurally characterized-yet this has not been achieved. Through simulation of the natural protein phospholamban and redesign of variants, we define a steric packing code underlying its assembly. Synthetic membrane proteins designed using this code and stabilized entirely by apolar side chains conform to the intended fold. Although highly stable, the steric complementarity required for their folding is surprisingly stringent. Structural informatics shows that the designed packing motif recurs across the proteome, emphasizing a prominent role for precise apolar packing in membrane protein folding, stabilization, and evolution.