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首页> 外文期刊>Journal of Molecular Biology >Synergistic Interactions between Aqueous and Membrane Domains of a Designed Protein Determine its Fold and Stability.
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Synergistic Interactions between Aqueous and Membrane Domains of a Designed Protein Determine its Fold and Stability.

机译：设计的蛋白质的水域和膜结构域之间的协同相互作用决定其折叠性和稳定性。

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摘要

Membrane-spanning proteins contain both aqueous and membrane-spanning regions, both of which contribute to folding and stability. To explore the interplay between these two domains we have designed and studied the assembly of coiled-coil peptides that span from the membrane into the aqueous phase. The membrane-spanning segment is based on MS1, a transmembrane coiled coil that contains a single Asn at a buried a position of a central heptad in its sequence. This Asn has been shown to drive assembly of the monomeric peptide in a membrane environment to a mixture of dimers and trimers. The coiled coil has now been extended into the aqueous phase by addition of water-soluble helical extensions. Although too short to fold in isolation, these helical extensions were expected to interact synergistically with the transmembrane domain and modulate its stability as well as its conformational specificity for forming dimers versus trimers. One design contains Asn at a position of the aqueous helical extension, which was expected to specify a dimeric state; a second peptide, which contains Val at this position, was expected to form trimers. The thermodynamics of assembly of the hybrid peptides were studied in micelles by sedimentation equilibrium ultracentrifugation. The aqueous helical extensions indeed conferred additional stability and conformational specificity to MS1 in the expected manner. These studies highlight the delicate interplay between membrane-spanning and water-soluble regions of proteins, and demonstrate how these different environments define the thermodynamics of a given specific interaction. In this case, an Asn in the transmembrane domain provided a strong driving force for folding but failed to specify a unique oligomerization state, while an Asn in the water-soluble domain was able to define specificity for a specific aggregation state as well as modulate stability.
机译：跨膜蛋白既包含水性区域，又包含跨膜区域，这两个区域均有助于折叠和稳定性。为了探索这两个结构域之间的相互作用，我们设计并研究了从膜到水相的卷曲螺旋肽的组装。跨膜段是基于MS1的，MS1是一种跨膜卷曲的线圈，在其中央序列的埋入位置中包含一个Asn。该Asn已经显示出在膜环境中驱动单体肽组装成二聚体和三聚体的混合物。现在，通过添加水溶性螺旋延伸物，将卷曲的螺旋物延伸至水相中。尽管太短以至于不能折叠，但是这些螺旋延伸预期与跨膜结构域协同相互作用，并调节其稳定性以及其构象特异性，以形成二聚体或三聚体。一种设计在水性螺旋延伸的位置包含Asn，预期该结构将指定为二聚态。第二个在此位置含有Val的肽预计会形成三聚体。通过沉淀平衡超速离心在胶束中研究了杂合肽组装的热力学。水性螺旋延伸确实以预期的方式赋予了MS1额外的稳定性和构象特异性。这些研究突出了跨膜蛋白和水溶性蛋白区域之间的微妙相互作用，并证明了这些不同的环境如何定义给定特定相互作用的热力学。在这种情况下，跨膜结构域中的Asn提供了强大的折叠驱动力，但未能指定独特的低聚状态，而水溶性结构域中的Asn能够定义特定聚集态的特异性以及调节稳定性。

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