A frequent, GxxxG-mediated, transmembrane association motif is optimized for the formation of interhelical Cα–H hydrogen bonds

Abstract

Carbon hydrogen bonds between Cα-H donors and carbonyl acceptors are frequently observed between transmembrane helices (Cα-H···O=C). Networks of these interactions occur often at helix−helix interfaces mediated by GxxxG and similar patterns. Cα-H hydrogen bonds have been hypothesized to be important in membrane protein folding and association, but evidence that they are major determinants of helix association is still lacking. Here we present a comprehensive geometric analysis of homodimeric helices that demonstrates the existence of a single region in conformational space with high propensity for Cα-H···O=C hydrogen bond formation. This region corresponds to the most frequent motif for parallel dimers, GAS right , whose best-known example is glycophorin A. The finding suggests a causal link between the high frequency of occurrence of GAS right and its propensity for carbon hydrogen bond formation. Investigation of the sequence dependency of the motif determined that Gly residues are required at specific positions where only Gly can act as a donor with its "side chain" Hα. Gly also reduces the steric barrier for nonGly amino acids at other positions to act as Cα donors, promoting the formation of cooperative hydrogen bonding networks. These findings offer a structural rationale for the occurrence of GxxxG patterns at the GAS right interface. The analysis identified the conformational space and the sequence requirement of Cα-H···O=C mediated motifs; we took advantage of these results to develop a structural prediction method. The resulting program, CATM, predicts ab initio the known high-resolution structures of homodimeric GAS right motifs at near-atomic level.interaction motifs | protein prediction

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“…The N-terminal TMH of HET-S plays a critical role in membrane targeting and toxicity (9). To investigate the role of the predicted HELLP TMH, we mutated two glycines, part of a putative GxxxG glycine-zipper motif, (a motif involved in TMH multimerization (21) into large hydrophobic residues (G9I and G13I) predicted to disrupt the glycine zipper (Fig. S1).…”

Evolutionary-guided de novo structure prediction of self-associated transmembrane helical proteins with near-atomic accuracy

“…Corroborating these observations, modelling techniques incorporating a weak CαH–O bond potential allowed for accurately predicting native right-handed TMH homodimer (RH) structures in native TMH docking simulation 23 or grid search from ideal helices 24 . However, a large majority of TMH homo-oligomers does not bear GASright motifs (that is, small-XXX-small residue motif identified at right-handed parallel TMH dimers with small being either Gly, alanine or serine 25 ) or are stabilized by a much larger diversity of physical interactions including Van der Waals (VDW), aromatic pi–pi, cation–pi and polar interactions 3,6,26–29 .…”

Structural determinants of human proton-coupled folate transporter oligomerization: role of GXXXG motifs and identification of oligomeric interfaces at transmembrane domains 3 and 6

“…GXXXG is one of the most frequently occurring transmembrane sequence motifs; the four-residue separation aligns the GXXXG glycines on one face of the helix, thus providing a flat surface for tight interactions between transmembrane α -helices [33–36]. The GXXXG motif has been linked to dimerization in membrane proteins [37–43].…”