The N-domain of shrew-1 harbors no ER translocation activity, but is able to mediate mitochondrial targeting. We wish to stress that this activity has been proven for the isolated N-domain in the context of the experimental setup used in the present study, and it needs further investigation to determine the conditions under which this activity is found in the context of the full-length signal peptide. Possibly this cryptic activity is revealed under certain physiological situations only. As an extension to the already known tandem signals like in the nicastrin or CYP2E1 precursors, our NtraC model provides a framework for cryptic signals. The domain model is of general relevance, as at least 62% of the known vertebrata proteins with a signal peptide exceeding 40 residues show an NtraC-organization. Although it remains Dabrafenib unclear if and under which conditions or regulatory control mitochondrial targeting of these proteins occurs, we were able show that NtraC-organized signal peptides can exhibit additional functions besides ER targeting or protein export. Prediction of such important structural elements has now become feasible. Due to its amphipathic nature, we further speculate that the Ndomain might be involved in dimerization or stabilization of shrew-1 in the plasma membrane or interaction with other proteins. Positively charged arginine residues in the N-domain could help the signal peptide to adopt its native conformation in the plasma membrane. It would thereby follow the ����positive inside rule���� and arrest the C-terminal part inside the membrane while being available for protein-protein interactions on the cytoplasmic side. The C-domain is sufficient for protein export via the ER, but not as effective as the full-length signal peptide. Most strikingly, the transition area which was first predicted to only link the N- to SB431542 side effects Cdomain, turned out to be essential for the full ER translocation activity of the C-domain. It is noteworthy that the transition area is the only part of the long signal peptides predicted to predominantly contain b-turns. Thus, turn formation seems to be not only a structural element separating the N- and C-domains, but a decisive feature of long signal peptides supporting the ER translocation activity of the C-domain. The NtraC model thereby explains earlier observations made for interleukin-15, which is subjected to different export rates depending on the length of its signal peptide. Our model also provides a rational explanation for membrane targeting of bacterial autotransporters, which possess long signal peptides: These are in accordance with our NtraC model, where the C-domain alone is sufficient for transport to the inner membrane but for proper processing the complete signal peptide is required.