Transmembrane helix dimerization: beyond the search for sequence motifs

Abstract

Studies of the dimerization of transmembrane (TM) helices have been ongoing for many years now, and have provided clues to the fundamental principles behind membrane protein (MP) folding. Our understanding of TM helix dimerization has been dominated by the idea that sequence motifs, simple recognizable amino acid sequences that drive lateral interaction, can be used to explain and predict the lateral interactions between TM helices in membrane proteins. But as more and more unique interacting helices are characterized, it is becoming clear that the sequence motif paradigm is incomplete. Experimental evidence suggests that the search for sequence motifs, as mediators of TM helix dimerization, cannot solve the membrane protein folding problem alone. Here we review the current understanding in the field, as it has evolved from the paradigm of sequence motifs into a view in which the interactions between TM helices are much more complex. This article is part of a Special Issue entitled: Membrane protein structure and function.

Figure 1. The membrane protein folding problem

In the pursuit of a solution to the membrane protein folding problem, it has been useful to separate the sequence-structure relationship into individual steps that can be experimentally characterized and quantitated on their own. For example, in this five stage model, sequence hydrophobicity drives partitioning and insertion, while lateral interactions between inserted segments drive dimerization and folding. In this review, we discuss what has been learned from studying the simplest folding reaction in membranes: the dimerization of membrane-spanning α-helices.

Figure 2. The abundance of several motifs in a typical membrane protein

The example protein shown here is the tetramer of aquaporin 1, but all membrane proteins have similar composition. A: All residues in the TM helices that are part of a pattern of SmxxxSm, where Sm = Gly, Ala, Thr or Ser, are shown in gray. SmxxxSm motifs that pack against one another (and thus might be involved in lateral interactions) are shown in black. Most motifs are not involved in interactions between helices. B. Leucine zipper-like motifs are very abundant in membrane proteins. Shown in the figure are all leucine, Ile or Val residues that are separated by an i, i+3 or i, i+4 pattern consistent with a coiled-coil or leucine zipper.

Figure 2. The abundance of several motifs in a typical membrane protein

The example protein shown here is the tetramer of aquaporin 1, but all membrane proteins have similar composition. A: All residues in the TM helices that are part of a pattern of SmxxxSm, where Sm = Gly, Ala, Thr or Ser, are shown in gray. SmxxxSm motifs that pack against one another (and thus might be involved in lateral interactions) are shown in black. Most motifs are not involved in interactions between helices. B. Leucine zipper-like motifs are very abundant in membrane proteins. Shown in the figure are all leucine, Ile or Val residues that are separated by an i, i+3 or i, i+4 pattern consistent with a coiled-coil or leucine zipper.

Figure 3. Examples of NMR dimer structures

A. The structure of the glycophorin A transmembrane TM homodimer (22). The side-chains of the seven residues that are most sensitive to mutations are shown (55). The degree of shading is proportional to the sensitivity of the dimer to mutations: black (highly sensitive: Gly79 and Gly83), dark gray (moderately sensitive: Leu75, Leu76 and Thr87), light gray (somewhat sensitive: Val80 and Val84). B. Structure of the BNIP3 homodimer (95) The side-chains of residues that are sensitive to mutations are shown (95). The degree of shading is proportional to the sensitivity of the dimer to mutations: black (highly sensitive: Ser172, His173, Ala176, Gly180, and Gly184), dark gray (moderately sensitive: Ile181 and Ile183), light gray (somewhat sensitive: Leu179 and Tyr181).

Figure 3. Examples of NMR dimer structures

A. The structure of the glycophorin A transmembrane TM homodimer (22). The side-chains of the seven residues that are most sensitive to mutations are shown (55). The degree of shading is proportional to the sensitivity of the dimer to mutations: black (highly sensitive: Gly79 and Gly83), dark gray (moderately sensitive: Leu75, Leu76 and Thr87), light gray (somewhat sensitive: Val80 and Val84). B. Structure of the BNIP3 homodimer (95) The side-chains of residues that are sensitive to mutations are shown (95). The degree of shading is proportional to the sensitivity of the dimer to mutations: black (highly sensitive: Ser172, His173, Ala176, Gly180, and Gly184), dark gray (moderately sensitive: Ile181 and Ile183), light gray (somewhat sensitive: Leu179 and Tyr181).