The ribosome to membrane route (RiMembR).

More than a third of the proteins of any cell are exported from the cytoplasm to cellular membranes or across them. This is an essential cellular process and over two thirds of drugs in current use target plasma membrane proteins. To reach the membrane, secretory proteins make use of aminoterminal signal peptides and novel signals that we recently identified in their mature domains. These uncharacterized signals are exposed only in natively unfolded states of mature domains. Cellular machineries would have to decipher this uncracked “non-native code”. RiMembR aims to identify the molecular nature of these signals and their interplay with signal peptides. Also, it will identify the global network of cellular factors that usher preproteins from the ribosome to the membrane, the order by which they act and how they sort them between a cytoplasmic folding and a secretory pathway fate. To this end we will employ protein to proteome, ensemble to single proteinlevel dissection. This involves a multi-disciplinary battery of tools that combine bioinformatics, biophysics, structural biology, mass spectrometry, molecular biology and enzymology and benefits from collaborations with international experts. RiMembR aims to elucidate a fundamental biological process by analyzing fascinating entirely new features of the process. This knowledgebase will constribute to our understanding of trafficking and misfolding disease and lays the foundation for novel anti-secretion antibiotics.