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Moving Proteins Into membranes and Organelles and Vesicular Traffic J a v a d F a s a J a m s h i d i U n i v e r s i t y o f M e d i c a l S c i e n c e s , N o v e m b e r 2 0 1 5 Protein Sorting A typical mammalian cell contains up to 10,000 different kinds of proteins About half of the different kinds of proteins produced in a cell are delivered to various membrane-bounded organelles within the cell or to the cell surface The delivery of newly synthesized proteins to their proper cellular destinations, usually referred to as protein targeting or protein sorting Different kinds of Protein Sorting Two very different kinds of processes: Signal-based targeting Vesicle-based trafficking Signal-based Targeting Targeting of a newly synthesized protein from the cytoplasm to an intracellular organelle Targeting can occur during translation or soon after synthesis of the protein is complete Proteins are sorted to the endoplasmic reticulum (ER), mitochondria, chloroplasts, peroxisomes, and nucleus by this general process Vesicle-based Trafficking Is known as the secretory pathway, and involves transport of proteins from the ER to their final destination For many proteins, including in the outside of the cell and integral membrane proteins are transported to the Golgi, lysosome, and plasma membrane by this process The secretory pathway begins in the ER; thus all proteins slated to enter the secretory pathway are initially targeted to this organelle Signal-based Targeting How a given protein could be directed to only one specific membrane?? How relatively large hydrophilic protein molecules could be translocated across a hydrophobic membrane without disrupting the bilayer?? Targeting Proteins to and Across the ER Membrane All soluble proteins that will eventually be secreted from the cell-as well as those destined for the lumen of the ER, Golgi, or lysosomes-are initially delivered to the ER lumen ER is the location where about one-third of the proteins in a typical cell fold into their native conformations Not all proteins that are targeted to the ER are actually secreted from the cell ER Signal Sequence A 16- to 30-residue ER signal sequence in the nascent protein directs the ribosome to the ER membrane An ER signal sequence typically is located at the N-terminus of the protein For most secretory proteins, the signal sequence is cleaved from the protein Signal Recognition Particle (SRP) A cytosolic ribnucleoprotein particle that transiently binds to both the ER signal sequence and large ribosomal subunit Targets the nascent protein-ribosome complex to the ER membrane by binding to the SRP receptor on the membrane The SRP is made up of six proteins bound to a 300-nucleotide RNA, which acts as a scaffold for the hexamer. Cotranslational translocation Topological Classes of Integral Membrane Proteins The topology ,number of times that its polypeptide spans the membrane and the orientation of protein The key elements of a protein that determine its topology are membrane-spanning segments themselves, which usually are a helices containing 20-25 hydrophobic amino acids Different Types of Transmembrane Proteins Positioning type I single-pass proteins Positioning type II single-pass proteins Protein Modifications, Folding, in the ER Membrane and soluble secretory proteins synthesized on the rough ER undergo four principal modifications: 1. Covalent addition and processing of carbohydrates (glycosylation) in the ER and Golgi 2. Formation of disulfide bonds in the ER, 3. Proper folding of polypeptide chains and assembly of multisubunit proteins in the ER, 4. Specific proteolytic cleavages in the ER, Golgi, and secretory vesicles. Direct Proteins to the Mitochondrial Matrix Amphipathic N-Terminal Signal Sequences Direct Proteins to the Mitochondrial Matrix located at the N-terminus, are usually 20-50 amino acids in length. Mitochondrial Protein Import Requires Outer-Membrane Receptors and Translocons in Both Membranes Nuclear Import/Export Proteins imported to or exported from the nucleus contain a specific amino acid sequence that functions as a nuclear localization signal (NLS) or a nuclear-export signal (NES) A cargo protein bearing an NES or NLS trans locates through nuclear pores bound to its cognate nuclear transport protein. Nuclear Import Vesicular Traffic Secretory pathway and the mechanisms of vesicular traffic that allow proteins to be secreted from the cell or delivered to the plasma membrane and the lysosome. The secretory pathway carries both soluble and membrane proteins from the ER to their final destination Transport of membrane and soluble proteins from one membrane-bounded compartment to another is mediated by transport vesicles Vesicular transport Protein Transport Through The Secretory Pathway Mutants In 5 Stages In The Secretory Pathway Different Coats in Vesicular Traffic Different Coats in Vesicular Traffic Mutants In 5 Stages In The Secretory Pathway Forward and Retrieval Pathways