Chapter 49: Intracellular Protein Traffic & Sorting

For the cytosolic branch, the text explains how specific targeting sequences direct proteins to mitochondria, peroxisomes, and the nucleus using sophisticated translocase systems. This includes the role of the TOM and TIM complexes for mitochondrial import, the use of nuclear localization signals (NLS) and importins driven by the Ran-GTPase cycle for nuclear transport, and the involvement of peroxisomal targeting sequences (PTS) which, when mutated, can lead to severe disorders like Zellweger syndrome. The chapter provides an in-depth analysis of the RER branch, where N-terminal signal peptides are recognized by the signal recognition particle (SRP) to facilitate cotranslational translocation through the Sec61 translocon. It elaborates on how proteins are inserted into membranes using stop-transfer signals and how the ER functions as a critical quality control compartment. Key concepts covered include the role of molecular chaperones like BiP and calnexin in protein folding, the activation of the unfolded protein response (UPR) during ER stress, and the disposal of misfolded proteins via ER-associated degradation (ERAD) and the ubiquitin-proteasome pathway. Furthermore, the text breaks down the mechanics of vesicular transport, describing how cargo is moved between the ER, Golgi apparatus, and plasma membrane using COPI, COPII, and clathrin-coated vesicles. This section highlights the molecular machinery of budding and fusion, including the regulatory roles of small GTPases like Sar1 and Rab, as well as the interactions between v-SNAREs and t-SNAREs that facilitate membrane docking. The chapter concludes by examining membrane assembly, lipid asymmetry, and the clinical significance of defects in protein transport, often referred to as conformational diseases or diseases of proteostasis deficiency.