Chirality-independent protein-protein recognition between transmembrane domains in vivo

Stereospecificity in protein-protein recognition and docking is an unchallenged dogma. Soluble proteins provide the main source of evidence for stereospecificity. In contrast, within the membrane little is known about the role of stereospecificity in the recognition process. Here, we have reassessed the stereospecificity of protein-protein recognition by testing whether it holds true for the well-defined glycophorin A (GPA) transmembrane domain in vivo. We found that the all-D amino acid GPA transmembrane domain and two all-D mutants specifically associated with an all-L GPA transmembrane domain, within the membrane milieu of Escherichia coli. Molecular dynamics techniques reveal a possible structural explanation to the observed interaction between all-D and all-L transmembrane domains. A very strong correlation was found between amino acid residues at the interface of both the all-L homodimer structure and the mixed L/D heterodimer structure, suggesting that the original interactions are conserved. The results suggest that GPA helix-helix recognition within the membrane is chirality-independent.