Phenylalanine Promotes Interaction of Transmembrane Domains via GxxxG Motifs

A Unique Phenylalanine in the Transmembrane Domain Strengthens Homodimerization of the Syndecan-2 Transmembrane Domain and Functionally Regulates Syndecan-2

“…Moreover, the presence of a phenylalanine in addition to the GXXXG motif enhances the self-association of the GpA TMD (8). Several other reports have confirmed that aromatic residues, either alone or near the GXXXG motif, can stabilize the TMD helix dimerization of membrane proteins (8,29,30 ). Therefore, we speculated that, as in the other studied receptors, phenylalanine might be involved in regulating the interaction strength of the syndecan TMDs.…”

“…Melnyk et al (7) reported that this is because interfacial residues around GXXXG motif also contribute to TMD-TMD affinity. Similarly, other researchers have reported that residues around the GXXXG motif participate in TMD-mediated aromatic and cation-interactions, helping to stabilize the TMD homodimer (8). Therefore, this TMD-TMD association appears to be regulated by the GXXXG motif and its surrounding amino acid residues, and this might affect TMDmediated signal transduction.…”

“…phenylalanine, tyrosine, and tryptophan) are involved in -and cation-interactions (28 -30), and the formation of such interactions between planar aromatic rings seems to be essential for the assembly of soluble proteins (31,32). Moreover, the presence of a phenylalanine in addition to the GXXXG motif enhances the self-association of the GpA TMD (8). Several other reports have confirmed that aromatic residues, either alone or near the GXXXG motif, can stabilize the TMD helix dimerization of membrane proteins (8,29,30 ).…”

Structure-Functional Insight Into Transmembrane Helix Dimerization

“…A separate important class of participants of specific TM helix association processes are π-π and cation-π aromatic interactions arising either between two aromatic residues or between a basic and an aromatic residue, respectively Unterreitmeier et al, 2007;Sal-Man et al, 2007). Interactions of aromatic rings of tryptophan, phenylalanine, tyrosine, and histidine residues and their self-association or interaction with protonated cation side chains of arginine, lysine, and histidine residues have been proposed to consist of van-derWaals and electrostatic forces complemented by correct packing geometry and interactions with the aromatic ring quadrupole moment.…”

“…Besides, the indole, phenol, and imidazole group of the aromatic residues can participate in hydrogen bonding across TM helix packing interface. Even though weak, C H-π interactions enhanced in the low dielectric membrane environment can be considered as additional interactions supporting specific TM helix association (Unterreitmeier et al, 2007). In addition, aromatic residues have a strong propensity to face phospholipids in the headgroup region and are thought to act as anchors for a membrane protein, influencing on helix tilting and hydrophobic matching in the membrane (Adamian et al, 2005).…”