Single-pass transmembrane proteins, also known as bitopic proteins, are ubiquitous across the domains of life. From transporters in E. coli to receptor activity modifying proteins (RAMPs) in humans, bitopic proteins affect the function of diverse functional protein complexes. However, determining whether a given bitopic protein can bind, and modulate, other membrane protein targets remains challenging, in part because little is known about the specificity of their interactions. Using the membranome database of bitopic proteins across species and the protein data bank (PDB), we investigated all known structures of bitopic proteins in humans and E. coli . Beyond a simple accounting of the number of structures and experimental methods used to determine them, we examined the fraction of the bitopic proteins’ sequences that are transmembrane, whether these transmembrane regions ended up in structures, and their known binding partners. This analysis enabled us to differentiate the sequence and binding selectivity of true auxiliary proteins (“auxiliary” to a transporter or G protein-coupled receptor, for instance) from those of other bitopic proteins that function independently of other binding partners (e.g., receptor tyrosine kinases, Toll-like receptors). Preliminary analysis reveals that of the 2505 human bitopic proteins, only 828 (16.5%) are represented by at least one PDB structure, and only 137 of those (5.5% of the total) have their transmembrane region in any PDB structure. The gaps and trends in data coming from this analysis point to future targets for understanding the structure and mechanism of membrane protein binding selectivity and function.
Smith et al. (Sun,) studied this question.