Complex Patterns of Histidine, Hydroxylated Amino Acids and the GxxxG Motif Mediate High-affinity Transmembrane Domain Interactions

Ionic Interactions Promote Transmembrane Helix–Helix Association Depending on Sequence Context

“…Figure 1 compares the affinities of these parental sequences to designed point mutants and a set of reference constructs [i.e., ΔTM (where the TMD has been deleted), AZ2, Table 1. TMD sequences containing ionizable residues, as isolated from a combinatorial library TMD designations were taken from Herrmann et al 32 Signal corresponds to relative β-gal activities (AZ2 = 1.0) elicited after expression in FHK12 cells that was induced by 0.0025% (wt/ vol) L-arabinose. Arg and Lys are underlaid in blue, Asp and Glu are underlaid in red, Gly residues (including the invariant Gly17 of the adjoining vector region) within GxxxG motifs are shaded, and invariant Leu residues are represented by dots.…”

“…Screening of that library had yielded a pool of high-affinity TMDs whose interaction depends on a motif where His binds to neighboring Gly, Ser, and/or Thr residues and cooperates with a C-terminal GxxxG motif. 32 Interestingly, that library screen had also yielded 11 high-affinity TMDs that all contain two or more ionizable residues of opposite charge, in addition to GxxxG. MalE complementation assays confirmed membrane embedding of these sequences.…”

Single-spanning transmembrane domains in cell growth and cell-cell interactions

“…Other characteristic motifs contain polar residues which contribute hydrogen bonds or charged residues which make static interactions. 43,44 A word of caution: the existence of one such short interaction short motifs in a TM sequence does not necessarily imply a significant interaction. For instance, about one third of GxxxG motifs in a non-redundant database of membrane protein structures To date more than 300 publications dealing with helical TM domain interactions of membrane proteins can be found, not counting studies of de novo designed sequences.…”

Two GxxxG-Like Motifs Facilitate Promiscuous Interactions of the Human ErbB Transmembrane Domains

“…25,26 Subsequent studies have shown that GG4-like motifs are often involved in TM helix interactions. [27][28][29][30] Interestingly, it was already noted almost 20 years ago that the single TM domains of several RTKs contain a characteristic GG4-like motif, and a function of this motif in TM signaling has been proposed. 31 Human ErbB1, ErbB2, and ErbB4 proteins possess two such motifs within their TM domains, which could be involved in stabilization of different dimeric structures, and a structural rearrangement of the TM helix interaction could be involved in ErbB signaling.…”