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Commentary 3381 Introduction All eukaryotic cells are surrounded by plasma membranes and contain elaborate organelles and a complex endomembrane system. These organelles provide distinct compartments for different metabolic activities. Protein translation is confined to only one of these compartments, the cytosol. The translocation of proteins is a fundamental requirement for proteins to be able to exert their functions in different organelles. Indeed, approximately half of the proteins generated by a cell have to be transported into or across at least one cellular membrane to reach their functional destination (Chacinska et al., 2009). The regulation of protein trafficking relies on information that is encoded within the protein sequence and occurs by two major mechanisms, namely co-translational and post-translational translocation (Rapoport, 2007; Schnell and Hebert, 2003; Wickner and Schekman, 2005). Proteins targeted to the mitochondria, peroxisomes or the nucleus are post-transcriptionally translocated (Fig. 1) (Schmidt et al., 2010; Suntharalingam and Wente, 2003; Terry et al., 2007; Wickner and Schekman, 2005; Wolf et al., 2010). Even though protein trafficking into each of these organelles involves distinct mechanisms, there are some common features, such as the presence of signal sequences, which are recognized by specific receptors, and the import through membrane-spanning pores. Whereas the transport systems for the post-translational translocation of proteins into the mitochondria rely on the activity of chaperones to provide unfolded polypeptide chains as translocation substrates (Rapoport, 2007; Schmidt et al., 2010), the nuclear envelope is perforated by nuclear pores that allow the passage of folded proteins either by simple diffusion or mediated by soluble transport receptors (Strambio-De-Castillia et al., 2010; Suntharalingam and Wente, 2003; Terry et al., 2007). By contrast, many other proteins, including those destined for the secretory pathway and integral membrane proteins, are transported into the endoplasmic reticulum (ER) during synthesis, a process known as co-translational translocation (Fig. 1) (Wickner and Schekman, 2005). Subcellular localization is essential to protein function and has been suggested as a means to achieve functional diversity and, at the same time, economize on protein design and synthesis (Butler and Overall, 2009). Subcellular localization determines the access of proteins to interacting partners and the post-translational modification machinery and enables the integration of proteins into functional biological networks. Aberrantly localized proteins have been linked to human diseases as diverse as Alzheimer’s disease, kidney stones and cancer. In this Commentary, we will, therefore, summarize our current knowledge on the mechanisms that regulate subcellular protein localization and those that have been implicated in the pathogenesis of human disease, and we will discuss emerging therapeutic strategies that target protein localization.
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