Fink Avner, Sal-Man Neta, Gerber Doron, Shai Yechiel
Department of Biological Chemistry, the Weizmann Institute of Science, Rehovot, 76100 Israel.
Biochim Biophys Acta. 2012 Apr;1818(4):974-83. doi: 10.1016/j.bbamem.2011.11.029. Epub 2011 Dec 3.
Protein-protein interactions within the membrane are involved in many vital cellular processes. Consequently, deficient oligomerization is associated with known diseases. The interactions can be partially or fully mediated by transmembrane domains (TMD). However, in contrast to soluble regions, our knowledge of the factors that control oligomerization and recognition between the membrane-embedded domains is very limited. Due to the unique chemical and physical properties of the membrane environment, rules that apply to interactions between soluble segments are not necessarily valid within the membrane. This review summarizes our knowledge on the sequences mediating TMD-TMD interactions which include conserved motifs such as the GxxxG, QxxS, glycine and leucine zippers, and others. The review discusses the specific role of polar, charged and aromatic amino acids in the interface of the interacting TMD helices. Strategies to determine the strength, dynamics and specificities of these interactions by experimental (ToxR, TOXCAT, GALLEX and FRET) or various computational approaches (molecular dynamic simulation and bioinformatics) are summarized. Importantly, the contribution of the membrane environment to the TMD-TMD interaction is also presented. Studies utilizing exogenously added TMD peptides have been shown to influence in vivo the dimerization of intact membrane proteins involved in various diseases. The chirality independent TMD-TMD interactions allows for the design of novel short d- and l-amino acids containing TMD peptides with advanced properties. Overall these studies shed light on the role of specific amino acids in mediating the assembly of the TMDs within the membrane environment and their contribution to protein function. This article is part of a Special Issue entitled: Protein Folding in Membranes.
膜内的蛋白质-蛋白质相互作用参与了许多重要的细胞过程。因此，寡聚化缺陷与已知疾病相关。这些相互作用可部分或完全由跨膜结构域（TMD）介导。然而，与可溶性区域不同，我们对控制膜嵌入结构域之间寡聚化和识别的因素的了解非常有限。由于膜环境独特的化学和物理性质，适用于可溶性片段之间相互作用的规则在膜内不一定有效。本综述总结了我们对介导TMD-TMD相互作用的序列的认识，其中包括保守基序，如GxxxG、QxxS、甘氨酸拉链和亮氨酸拉链等。该综述讨论了极性、带电荷和芳香族氨基酸在相互作用的TMD螺旋界面中的特定作用。总结了通过实验方法（ToxR、TOXCAT、GALLEX和FRET）或各种计算方法（分子动力学模拟和生物信息学）来确定这些相互作用的强度、动力学和特异性的策略。重要的是，还介绍了膜环境对TMD-TMD相互作用的贡献。利用外源添加的TMD肽进行的研究已证明会在体内影响参与各种疾病的完整膜蛋白的二聚化。不依赖手性的TMD-TMD相互作用使得能够设计具有先进特性的新型含短d-和l-氨基酸的TMD肽。总体而言，这些研究揭示了特定氨基酸在介导膜环境中TMD组装及其对蛋白质功能贡献方面的作用。本文是名为：膜中蛋白质折叠的特刊的一部分。
