The biogenesis of short secretory proteins: pathways for posttranslational translocation at the mammalian endoplasmic reticulum

In contrast to the previously held view that mammalian secretory proteins are synthesised via a co-translational, signal recognition particle-dependent, pathway, recent studies show a substantial proportion exploit one or more distinct, post-translational, routes (Johnson et al., 2012; Lakkar et al., 2012; Shao and Hegde, 2011). Whilst they posses a typical, N-terminal endoplasmic reticulum (ER) targeting signal, one feature of such precursors is that they are unusually short, and hence unable to exploit the co-translational route. Our own work has focused on potential similarities between the biogenesis of short secretory proteins and that of tail-anchored membrane proteins, another group that are post-translationally inserted into the ER membrane (Rabu et al., 2009; Leznicki et al., 2010). We find clear evidence that the TRC40 pathway can deliver both tail-anchored and short secretory proteins to the ER (Johnson et al., 2012). Equally, whilst short secretory proteins are then translocated into the ER via the Sec61 complex (Johnson et al., 2012; Lakkar et al., 2012); this component plays no rule in the membrane insertion of tail-anchored proteins (Rabu et al., 2009). The goal of this PhD project will be to exploit our existing experimental platforms and analytical systems in order to investigate the contribution of different cytosolic components during the delivery of short secretory proteins (Johnson et al., 2012; Shao and Hegde, 2011). In addition we will establish the molecular mechanisms by which the Sec61 complex can efficiently transport a polypeptide chain across the ER membrane in the absence of ongoing protein synthesis. This work will provide new insights into the synthesis of important secretory proteins that play a range of important roles for normal human health and development.