Which kinds of TMD-TMD interfaces were invented by nature?



There is no reliable method to predict if a particular TMD forms a strong dimer. We have used the ToxR assay in combination with proteome-wide analyses to empirically identify human TMDs that show strong self-interaction. Encouragingly, we have found that human TMDs with strong interaction tend to be more conserved on one side of the transmembrane helix. This sidedness can is measured as a conservation moment (CM). However the link between conservation and TMD dimer interfaces is not fully understood. Are the highly conserved amino acids in the high CM TMDs always involved in dimerization? Can conservation help pinpoint the exact motifs that are involved in dimerization? For example, if a TMD contains two GxxxG “glycine-zipper” motifs, can conservation help identify the one important for dimerization?

The concept:

The ToxR assay of TMD-TMD interaction combined with scanning mutagenesis is a powerful method to empirically characterize TMD dimer interfaces. By analysing human TMDs with a high conservation moment, novel self-interaction interfaces can be identified. A detailed analysis of amino acid conservation, motifs, and predicted structures allows us to identify features common to the amino acids at the dimer interface. These features can then be incorporated into future models and prediction algorithms, increasing our ability to predict and understand the TMD-TMD interactions, and therefore their role in living cells.