Homotypic Interaction and Amino Acid Distribution of Unilaterally Conserved Transmembrane Helices

Formation of non-covalent functional complexes of integral membrane proteins is frequently supported by sequence-specific interaction of their transmembrane helices. Here, we aligned human single-span membrane proteins with orthologs from other eukaryotes. We find that almost half of the human single-span membrane proteins contain a transmembrane helix that exhibits significant non-random unilateral conservation. Furthermore, unilateral conservation of transmembrane domains (TMDs) correlates well with their ability to self-interact. Glycine, polar non-ionizable, and aromatic amino acids are overrepresented in conserved versus non-conserved helix faces. Hence, our genome-wide analysis indicates that these amino acid types generally support interaction of single-span membrane protein TMDs. [Display omitted] ► Dimerization of integral membrane proteins is supported by transmembrane helices. ► We find many transmembrane helices with non-random unilateral sequence conservation. ► Unilateral conservation of TMDs correlates well with their ability to self-interact. ► Conserved TMD sides prefer small, polar, and aromatic amino acids. ► Thus, many human membrane proteins oligomerize via their TMDs.