Transmembrane proteins comprise approximately 30% of all cellular proteins and play critical roles in many biological processes. Most membrane-spanning protein segments are hydrophobic a-helical structures, whose transmembrane stability is largely independent of their amino acid sequence. Nevertheless, the sequence of transmembrane domains confers specificity on these Fuziline protein segments because the amino acid side-chains can engage in highly specific protein-protein interactions in the membrane, which determine protein oligomerization, folding, and activity. It is therefore important to understand the molecular basis for specific protein-protein interactions between transmembrane domains. Transmembrane domains can be difficult to study due to their localization in membranes and poor solubility in aqueous environments. We have developed genetic methods to circumvent some of the challenges posed by transmembrane domains and used these methods to isolate small, Yunaconitine artificial transmembrane proteins that modulate native cellular transmembrane proteins in living cells. Using the dimeric 44-amino acid bovine papillomavirus E5 oncoprotein as a scaffold, we have generated libraries expressing hundreds of thousands of artificial proteins with randomized transmembrane domains and selected biologically active proteins from these libraries. Because the E5 protein is essentially an isolated transmembrane domain, it is an ideal scaffold for constructing such transmembrane protein libraries. Previously, we used this approach to isolate small transmembrane proteins that activate the natural cellular target of the E5 protein, the platelet-derived growth factor beta receptor. We also isolated small transmembrane proteins that activate the human erythropoietin receptor or down-regulate CCR5, a multi-pass transmembrane G protein-coupled receptor and HIV entry co-receptor. Our success in reprogramming E5 to recognize completely different targets highlights the ability of transmembrane domains to engage in highly specific inter-helical interactions that can modulate complex biological processes. We designate these small transmembrane proteins ‘‘traptamers,’’ for transmembrane aptamers.