Transmembrane Helix-Helix Interactions in the Human Single-Span Membrane Proteome

Most integral membrane proteins form non-covalent functional complexes that are frequently supported by sequence-specific interaction of transmembrane helices [1]. It has been suggested that non-covalent membrane protein multimerization may substitute for the frequently observed multi-domain organization of soluble proteins [2,3]. Here, we aligned human single-span membrane proteins with orthologs from other eukaryotes and examined the sidedness of transmembrane helices. We find that almost half of the human single-span membrane proteins possess a transmembrane helix with unilateral conservation. We propose unilateral conservation in most cases to indicate the presence of a helix-helix interface as well as the strength of interaction since it correlates well with experimentally determined self-affinities. This suggests that unilateral conservation is a good predictor of homotypic TMD interaction and underlines that transmembrane helix-helix interactions significantly contribute to protein assembly in the human single-span membrane proteome.[1] Langosch D, Arkin IT (2009) Interaction and conformational dynamics of membrane-spanning protein helices. Protein Sci 18:1343-1358.[2] Grasberger B, Minton AP, DeLisi C, Metzger H (1986) Interaction between proteins localized in membranes. Proc Natl Acad Sci USA 83:6258-6262.[3] Liu Y, Gerstein M, Engelman DM (2004) Transmembrane protein domains rarely use covalent domain recombination as an evolutionary mechanism. Proc Natl Acad Sci USA 101:3495-3497.