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Secretory pathway way to the surface Vesicular traffic ER to Golgi and Beyond Synthesis of proteins and lipids with translocation to ER or insertion into ER membranes Modifications Proteins co-translational and post-translational in rough ER and Golgi Lipids mostly posttranslational glycosylation Delivery to destination place Outside Cell membrane or membranes of the organelles Concerns about delivery Has to be specific for an organelle Different proteins have different destinations Has to preserve identity of the organelle Has to be free of components leaking from ER or Golgi Steps in vesicular transport Cargo selection what goes where Recruitment and sorting Container formation Vesicle formation and pinching Addressing Targeting (docking) and fusion with the destination compartment Delivery to the proper address Destinations Remember about recycling too ER Golgi Golgi surface (exocytosis) Constitutive Regulated Golgi lysosomes Golgi endosomes lysosomes Golgi back to ER Within Golgi Surface endosomes lysosomes (endocytosis) Major players Cargo selection Recruitment signals Sorting motifs Container - vesicles Address - coat proteins specific for different destinations Small GTPases - energy Regulate timing and fidelity Docking complex 1 Cargo selection Budding vesicle contains only proteins destined for transport to particular destination That means that resident components of organelle of origin (ER or Golgi) as well as proteins going to different destinations have to be excluded !!! Cargo selection Sorting motifs Where to go Diacidic motif linked to tyrosine for transport from ER to Golgi Aspartic acid X- glutamic acid linked to tyrosine Tyrosine does not have to be near Vesicle formation and budding ER to Golgi Mediated by COPII Catalyzed by GTPase Sar1 Cargo selection Recruitment signals on cargo proteins To go or not to go Short peptide sequences in protein sequence Only proteins that have recruitment signals will go, the rest will stay in the ER or Golgi (because both ER and Golgi have their own proteins such as modification enzymes and they do not want to lose them) Coat proteins 3 types of coat = destination COPII from rough ER to Golgi Clathrin from Golgi to the surface via endosome and from surface to endosome lysosome COPI recycling in Golgi and from Golgi back to ER Coat assembly and budding Activation of GTPase Active Sar1 recruits cargo through recognition of sorting motifs Formation of prebudding complex 2 Coat assembly and budding Addition vesicular ID (where to go because cargo is inside, sorting motifs no longer visible) Coat assembly Membrane invagination bud formation What has to be taken care of during delivery Fidelity Recognition signals both on vesicle and destination organelle Vesicular ID Must be included during vesicle formation Homing device Coat assembly and budding Vesicle pinching and release Coat depolymerization vesicular ID (destination address exposed) Vesicle is moved to final destination and docked Delivery of intracellular vesicles Similar for all vesicles regardless of coat Fusion occurs after depolymerization of the coats Two steps Targeting to appropriate place Fusion Docking complex on the destination membrane Vesicle targeting Depolymerization of coat uncovers vesicular ID = tethering factors and (vesicular) V-SNARE proteins on the vesicular membrane Targeting components have to be a part of a vesicle Tethering factors Have long extended coil-coiled domains Bind to similar domains on docking complex In COPII mediated targeting P115 on the vesicle GM130/GRASP65 on Golgi 3 Vesicle targeting V-SNARE targets the vesicle to its correct membrane fusion partner T-SNARE (target) The specificity of the interaction ascertains proper targeting Vesicle docking V and T SNARE work by interactions between arginines (R) and glutamines (Q) Therefore they can be called R and Q SNARES Cis-SNARE pairing 4 helix structure of coil-coiled domains Regulated fusion of vesicles with cell membrane Usually the signal for fusion is increased concentration of intracellular calcium Synaptotagmin is the key Ca2+ sensing protein Fusion After docking the vesicle waits for signal to fuse with the target membrane Membranes merge Following fusion the SNARE complexes are disassembled Calcium dependence of fusion process Ca 2+ can come from outside of the cells through voltage dependent calcium channels or from intracellular calcium stores (in response to membrane depolarization in excitable cells) Ca2+ ions activate synaptotagmin that starts fusion (exocytosis) Extra Ca2+ ions are rapidly removed from cytosol by Ca2+ ATPases (pumps) Fusion If the protein was inside ER it is secreted (inside of ER becomes the outside of the cell) If the protein was inserted in the ER membrane it is now in the destination membrane The sidedness of the membrane is preserved through the entire process Parts of protein that faced cytosol are still facing cytosol Parts that faced inside of ER are now on the outside of the cell or facing inside of the organelle 4 Progression from ER to Golgi Movement through Golgi stack Cis medial trans Cisternal progression (maturation) with subsequent recycling of Golgi enzymes Recycling within Golgi and back to ER Golgi enzymes are retained in Golgi by specific sequences localized within membrane domains and retrograde transport Recycling within Golgi and back to ER COPI mediated Polymerize and depolymerize similar to COPII Incorporation into COPI coated vesicles is based on dilysine sorting motif KKxxCOOH Divergence of cargo at the transGolgi network Transport to plasma membrane exocytosis Now from Golgi there are many choices Sorting based on Protein motifs Physical properties such as aggregation Geometric consideration 5 Constitutive secretion Regulated secretion Unregulated , constant Whatever was not retained goes to the surface No signal necessary No known coat proteins have been identified Membrane tubules rather than vesicles carry cargo to the surface Regulated secretion Sorting controlled by selective protein aggregation with selectogranins in transGolgi Vesicle waits for a signal to merge with the membrane For proteins that are not needed all the time Hormones Transmitters Cytokines Protein sorting in polarized cells Proteins are directly sorted to apical and basolateral surfaces of the polarized cells or Apical membrane proteins are endocytosed and moved across the cell (transcytosis) Transcytosis 6

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