Transmembrane domains interactions within the membrane milieu: Principles, advances and challenges

Avner Fink, Neta Sal-Man, Doron Gerber, Yechiel Shai

Research output: Contribution to journalReview articlepeer-review

98 Scopus citations


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.

Original languageEnglish
Pages (from-to)974-983
Number of pages10
JournalBiochimica et Biophysica Acta - Biomembranes
Issue number4
StatePublished - Apr 2012
Externally publishedYes

Bibliographical note

Funding Information:
Yechiel Shai has The Harold S. and Harriet B. Brady Professorial Chair in Cancer Research. This study was supported in part by the Israel Science Foundation , Josef Cohn Minerva Center for Biomembrane Research and the Minerva Foundation .


  • Helix-helix interaction
  • Recognition within the membrane
  • ToxR
  • Transmembrane domain


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