COPII components (known as Sec13p, Sec23p, Sec24p, Sec31p, and Sar1p in yeast) traffic cargo from the endoplasmic reticulum to the ER-Golgi intermediate compartment (ERGIC). COPII-coated vesicles were originally discovered in the yeast Saccharomyces cerevisiae using genetic approaches coupled with a cell-free assay. The mammalian counterpart of this pathway is represented here. Newly synthesized proteins destined for secretion are sorted into COPII-coated vesicles at specialized regions of the ER. These vesicles leave the ER, become uncoated and subsequently fuse with the ERGIC membrane.
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Allan BB, Moyer BD, Balch WE.; ''Rab1 recruitment of p115 into a cis-SNARE complex: programming budding COPII vesicles for fusion.''; PubMedEurope PMCScholia
Bhandari D, Zhang J, Menon S, Lord C, Chen S, Helm JR, Thorsen K, Corbett KD, Hay JC, Ferro-Novick S.; ''Sit4p/PP6 regulates ER-to-Golgi traffic by controlling the dephosphorylation of COPII coat subunits.''; PubMedEurope PMCScholia
Wang T, Grabski R, Sztul E, Hay JC.; ''p115-SNARE interactions: a dynamic cycle of p115 binding monomeric SNARE motifs and releasing assembled bundles.''; PubMedEurope PMCScholia
Hay JC, Chao DS, Kuo CS, Scheller RH.; ''Protein interactions regulating vesicle transport between the endoplasmic reticulum and Golgi apparatus in mammalian cells.''; PubMedEurope PMCScholia
Sprangers J, Rabouille C.; ''SEC16 in COPII coat dynamics at ER exit sites.''; PubMedEurope PMCScholia
Dascher C, Balch WE.; ''Mammalian Sly1 regulates syntaxin 5 function in endoplasmic reticulum to Golgi transport.''; PubMedEurope PMCScholia
Hughes H, Budnik A, Schmidt K, Palmer KJ, Mantell J, Noakes C, Johnson A, Carter DA, Verkade P, Watson P, Stephens DJ.; ''Organisation of human ER-exit sites: requirements for the localisation of Sec16 to transitional ER.''; PubMedEurope PMCScholia
Nakamura N, Lowe M, Levine TP, Rabouille C, Warren G.; ''The vesicle docking protein p115 binds GM130, a cis-Golgi matrix protein, in a mitotically regulated manner.''; PubMedEurope PMCScholia
Malhotra V, Erlmann P, Nogueira C.; ''Procollagen export from the endoplasmic reticulum.''; PubMedEurope PMCScholia
Hammond AT, Glick BS.; ''Dynamics of transitional endoplasmic reticulum sites in vertebrate cells.''; PubMedEurope PMCScholia
Gordon DE, Bond LM, Sahlender DA, Peden AA.; ''A targeted siRNA screen to identify SNAREs required for constitutive secretion in mammalian cells.''; PubMedEurope PMCScholia
Südhof TC, Rothman JE.; ''Membrane fusion: grappling with SNARE and SM proteins.''; PubMedEurope PMCScholia
Malhotra V, Erlmann P.; ''Protein export at the ER: loading big collagens into COPII carriers.''; PubMedEurope PMCScholia
Müller JM, Rabouille C, Newman R, Shorter J, Freemont P, Schiavo G, Warren G, Shima DT.; ''An NSF function distinct from ATPase-dependent SNARE disassembly is essential for Golgi membrane fusion.''; PubMedEurope PMCScholia
Yorimitsu T, Sato K.; ''Insights into structural and regulatory roles of Sec16 in COPII vesicle formation at ER exit sites.''; PubMedEurope PMCScholia
Whiteheart SW, Matveeva EA.; ''Multiple binding proteins suggest diverse functions for the N-ethylmaleimide sensitive factor.''; PubMedEurope PMCScholia
Shah N, Colbert KN, Enos MD, Herschlag D, Weis WI.; ''Three αSNAP and 10 ATP molecules are used in SNARE complex disassembly by N-ethylmaleimide-sensitive factor (NSF).''; PubMedEurope PMCScholia
Fuchs E, Haas AK, Spooner RA, Yoshimura S, Lord JM, Barr FA.; ''Specific Rab GTPase-activating proteins define the Shiga toxin and epidermal growth factor uptake pathways.''; PubMedEurope PMCScholia
Hui N, Nakamura N, Sönnichsen B, Shima DT, Nilsson T, Warren G.; ''An isoform of the Golgi t-SNARE, syntaxin 5, with an endoplasmic reticulum retrieval signal.''; PubMedEurope PMCScholia
Mancias JD, Goldberg J.; ''Structural basis of cargo membrane protein discrimination by the human COPII coat machinery.''; PubMedEurope PMCScholia
Supek F, Madden DT, Hamamoto S, Orci L, Schekman R.; ''Sec16p potentiates the action of COPII proteins to bud transport vesicles.''; PubMedEurope PMCScholia
Kung LF, Pagant S, Futai E, D'Arcangelo JG, Buchanan R, Dittmar JC, Reid RJ, Rothstein R, Hamamoto S, Snapp EL, Schekman R, Miller EA.; ''Sec24p and Sec16p cooperate to regulate the GTP cycle of the COPII coat.''; PubMedEurope PMCScholia
Watson P, Townley AK, Koka P, Palmer KJ, Stephens DJ.; ''Sec16 defines endoplasmic reticulum exit sites and is required for secretory cargo export in mammalian cells.''; PubMedEurope PMCScholia
Yamasaki A, Menon S, Yu S, Barrowman J, Meerloo T, Oorschot V, Klumperman J, Satoh A, Ferro-Novick S.; ''mTrs130 is a component of a mammalian TRAPPII complex, a Rab1 GEF that binds to COPI-coated vesicles.''; PubMedEurope PMCScholia
Saito K, Yamashiro K, Shimazu N, Tanabe T, Kontani K, Katada T.; ''Concentration of Sec12 at ER exit sites via interaction with cTAGE5 is required for collagen export.''; PubMedEurope PMCScholia
Cai H, Yu S, Menon S, Cai Y, Lazarova D, Fu C, Reinisch K, Hay JC, Ferro-Novick S.; ''TRAPPI tethers COPII vesicles by binding the coat subunit Sec23.''; PubMedEurope PMCScholia
Johnson A, Bhattacharya N, Hanna M, Pennington JG, Schuh AL, Wang L, Otegui MS, Stagg SM, Audhya A.; ''TFG clusters COPII-coated transport carriers and promotes early secretory pathway organization.''; PubMedEurope PMCScholia
Brunet S, Sacher M.; ''In sickness and in health: the role of TRAPP and associated proteins in disease.''; PubMedEurope PMCScholia
Hay JC, Klumperman J, Oorschot V, Steegmaier M, Kuo CS, Scheller RH.; ''Localization, dynamics, and protein interactions reveal distinct roles for ER and Golgi SNAREs.''; PubMedEurope PMCScholia
Otto H, Hanson PI, Jahn R.; ''Assembly and disassembly of a ternary complex of synaptobrevin, syntaxin, and SNAP-25 in the membrane of synaptic vesicles.''; PubMedEurope PMCScholia
Moyer BD, Allan BB, Balch WE.; ''Rab1 interaction with a GM130 effector complex regulates COPII vesicle cis--Golgi tethering.''; PubMedEurope PMCScholia
Witte K, Schuh AL, Hegermann J, Sarkeshik A, Mayers JR, Schwarze K, Yates JR, Eimer S, Audhya A.; ''TFG-1 function in protein secretion and oncogenesis.''; PubMedEurope PMCScholia
Brandizzi F, Barlowe C.; ''Organization of the ER-Golgi interface for membrane traffic control.''; PubMedEurope PMCScholia
Dancourt J, Barlowe C.; ''Protein sorting receptors in the early secretory pathway.''; PubMedEurope PMCScholia
Szul T, Sztul E.; ''COPII and COPI traffic at the ER-Golgi interface.''; PubMedEurope PMCScholia
Brandon E, Szul T, Alvarez C, Grabski R, Benjamin R, Kawai R, Sztul E.; ''On and off membrane dynamics of the endoplasmic reticulum-golgi tethering factor p115 in vivo.''; PubMedEurope PMCScholia
Lord C, Ferro-Novick S, Miller EA.; ''The highly conserved COPII coat complex sorts cargo from the endoplasmic reticulum and targets it to the golgi.''; PubMedEurope PMCScholia
Cao X, Barlowe C.; ''Asymmetric requirements for a Rab GTPase and SNARE proteins in fusion of COPII vesicles with acceptor membranes.''; PubMedEurope PMCScholia
Flanagan JJ, Barlowe C.; ''Cysteine-disulfide cross-linking to monitor SNARE complex assembly during endoplasmic reticulum-Golgi transport.''; PubMedEurope PMCScholia
Miller E, Antonny B, Hamamoto S, Schekman R.; ''Cargo selection into COPII vesicles is driven by the Sec24p subunit.''; PubMedEurope PMCScholia
Zhao C, Smith EC, Whiteheart SW.; ''Requirements for the catalytic cycle of the N-ethylmaleimide-Sensitive Factor (NSF).''; PubMedEurope PMCScholia
Mayer A, Wickner W, Haas A.; ''Sec18p (NSF)-driven release of Sec17p (alpha-SNAP) can precede docking and fusion of yeast vacuoles.''; PubMedEurope PMCScholia
Kanapin A, Batalov S, Davis MJ, Gough J, Grimmond S, Kawaji H, Magrane M, Matsuda H, Schönbach C, Teasdale RD, Yuan Z, RIKEN GER Group, GSL Members.; ''Mouse proteome analysis.''; PubMedEurope PMCScholia
Haas AK, Yoshimura S, Stephens DJ, Preisinger C, Fuchs E, Barr FA.; ''Analysis of GTPase-activating proteins: Rab1 and Rab43 are key Rabs required to maintain a functional Golgi complex in human cells.''; PubMedEurope PMCScholia
Mossessova E, Bickford LC, Goldberg J.; ''SNARE selectivity of the COPII coat.''; PubMedEurope PMCScholia
Xu D, Joglekar AP, Williams AL, Hay JC.; ''Subunit structure of a mammalian ER/Golgi SNARE complex.''; PubMedEurope PMCScholia
Miller EA, Beilharz TH, Malkus PN, Lee MC, Hamamoto S, Orci L, Schekman R.; ''Multiple cargo binding sites on the COPII subunit Sec24p ensure capture of diverse membrane proteins into transport vesicles.''; PubMedEurope PMCScholia
Beetz C, Johnson A, Schuh AL, Thakur S, Varga RE, Fothergill T, Hertel N, Bomba-Warczak E, Thiele H, Nürnberg G, Altmüller J, Saxena R, Chapman ER, Dent EW, Nürnberg P, Audhya A.; ''Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure.''; PubMedEurope PMCScholia
Söllner T, Bennett MK, Whiteheart SW, Scheller RH, Rothman JE.; ''A protein assembly-disassembly pathway in vitro that may correspond to sequential steps of synaptic vesicle docking, activation, and fusion.''; PubMedEurope PMCScholia
Barrowman J, Bhandari D, Reinisch K, Ferro-Novick S.; ''TRAPP complexes in membrane traffic: convergence through a common Rab.''; PubMedEurope PMCScholia
Bhattacharyya D, Glick BS.; ''Two mammalian Sec16 homologues have nonredundant functions in endoplasmic reticulum (ER) export and transitional ER organization.''; PubMedEurope PMCScholia
Stephens DJ, Lin-Marq N, Pagano A, Pepperkok R, Paccaud JP.; ''COPI-coated ER-to-Golgi transport complexes segregate from COPII in close proximity to ER exit sites.''; PubMedEurope PMCScholia
Weide T, Bayer M, Köster M, Siebrasse JP, Peters R, Barnekow A.; ''The Golgi matrix protein GM130: a specific interacting partner of the small GTPase rab1b.''; PubMedEurope PMCScholia
Sato K, Nakano A.; ''Mechanisms of COPII vesicle formation and protein sorting.''; PubMedEurope PMCScholia
Bentley M, Liang Y, Mullen K, Xu D, Sztul E, Hay JC.; ''SNARE status regulates tether recruitment and function in homotypic COPII vesicle fusion.''; PubMedEurope PMCScholia
Lord C, Bhandari D, Menon S, Ghassemian M, Nycz D, Hay J, Ghosh P, Ferro-Novick S.; ''Sequential interactions with Sec23 control the direction of vesicle traffic.''; PubMedEurope PMCScholia
Shorter J, Beard MB, Seemann J, Dirac-Svejstrup AB, Warren G.; ''Sequential tethering of Golgins and catalysis of SNAREpin assembly by the vesicle-tethering protein p115.''; PubMedEurope PMCScholia
Ong YS, Tang BL, Loo LS, Hong W.; ''p125A exists as part of the mammalian Sec13/Sec31 COPII subcomplex to facilitate ER-Golgi transport.''; PubMedEurope PMCScholia
Seemann J, Jokitalo EJ, Warren G.; ''The role of the tethering proteins p115 and GM130 in transport through the Golgi apparatus in vivo.''; PubMedEurope PMCScholia
Computational analysis suggests that ~25% of the proteome may be exported from the ER in human cells (Kanapin et al, 2003). These cargo need to be recognized and concentrated into COPII vesicles, which range in size from 60-90 nm, and which move cargo from the ER to the ERGIC in mammalian cells (reviewed in Lord et al, 2013; Szul and Sztul, 2011). Recognition of transmembrane cargo is mediated by interaction with one of the 4 isoforms of SEC24, a component of the inner COPII coat (Miller et al, 2002; Miller et al, 2003; Mossessova et al, 2003; Mancias and Goldberg, 2008). Soluble cargo in the ER lumen is concentrated into COPII vesicles through interaction with a receptor of the ERGIC-53 family, the p24 family or the ERV family. Each of these families of transmembrane receptors interact with cargo through their lumenal domains and with components of the COPII coat with their cytoplasmic domains and are packaged into the COPII vesicle along with the cargo. The receptors are subsequently recycled to the ER in COPI vesicles through retrograde traffic (reviewed in Dancourt and Barlowe, 2010). Packaging of large cargo such as fibrillar collagen depends on the transmembrane accessory factors MIA3 (also known as TANGO1) and CTAGE5. Like the ERGIC, p24 and ERV cargo receptors, MIA3 and CTAGE5 interact both with the collagen cargo and with components of the COPII coat. Unlike the other cargo receptors, however, MIA3 and CTAGE5 are not loaded into the vesicle but remain in the ER membrane (reviewed in Malhotra and Erlmann, 2011; Malhotra et al, 2015).
Once loaded the vesicles become fully sculpted, pinch off from the ER and bud into the cytosol. Budding depends on SAR1:GTPase activity and likely releases the SEC16 complex. SAR1:GTPase activity may result in partial uncoating of the emerging vesicle, allowing SEC23 to be exposed for subsequent TRAPPCII binding.
SAR1-GDP is recruited to the ER membrane by the transmembrane GEF (Guanine nucleotide exchange factor) PREB (also known as SEC12), where it is converted to SAR1-GTP. PREB itself is recruited to ER exit sites through interaction with CTAGE5.
The outer coat proteins SEC13 and SEC31A are thought to exist in a cytosolic heterohexamer with SEC23IP and are recruited to the ER through interaction with pre-bound SEC23-SEC24 complexes (Stephens et al, 2000; Hammond and Glick, 2000; Ong et al, 2010; reviewed in Szul and Sztul, 2011). v-SNAREs such as the SEC22 proteins are also incorporated into the emerging vesicle through interactions with components of the COPII coat (Xu et al, 2000; Mancias and Goldberg, 2008; Gordon et al, 2010; reviewed in Szul and Sztul, 2011; Lord et al, 2013).
The multimeric SEC16 complex marks sites of ER exit (ERES) and helps to localize nascent COPII coat complexes through interaction with SEC23 and SAR1 (Battacharyya et al, 2007; Watson et al, 2006; Hughes et al, 2009; Yorimitsu and Sato, 2012; reviewed in Sprangers and Rabouille, 2015). SEC16 may help to prevent premature dissociation of the COPII coats after activation of SEC13 GTPase (Supek et al, 2002; Kung et al, 2012). SEC16 functions with hexameric TFG1, which is recruited to the ERES through direct interaction with SEC16 and is required for cargo traffic out of the ER and for organization of the ER-to-ERGIC boundary (Witte et al, 2001; Beetz et al, 2012; Johnson et al, 2015).
Protein protein interactions involving activated RAB1:GTP help dock the ER-derived vesicle on the cis-Golgi membrane (reviewed in Lord et al, 2013) . Independently, RAB:GTP interacts with both the USO1 homodimer (a long coiled coil tethering factor also known as p115) and the GOLGA2 component of the GOLGA2:GORASP1 complex on the cis-Golgi membrane (Allan et al, 2000; Moyer et al, 2001; Weide et al, 2001). USO1 also contacts GOLGA2 directly (Nakamura et al, 1997; Seeman et al, 2000). t-SNARES such as STX5, GOSR1and GOSR2 also participate in this complex on the cis-ERGIC membrane (Brandon et al, 2006; Shorter et al, 2002; reviewed in Brandizzi and Barlowe, 2013).
PP6 dephosphorylates released coat proteins including SEC24, SEC31 and SEC23, allowing them to recycle for further rounds of vesicle budding from the ER (Lord et al, 2011; Bhandari et al, 2013).
After membrane fusion, the cis-SNARE complex is dissociated in an ATP-dependent fashion by the AAA protein NSF in conjunction with SNAP proteins (Mayer et al, 1996; Sollner et al, 1993; reviewed in Jahn and Scheller, 2006; Sudhof and Rothman, 2009).
NSF-dependent hydrolysis of ATP is required to disassociate the cis-SNARE complex, releasing the SNAREs for further rounds of membrane fusion (Mayer et al, 1996; Muller et al, 1999; Muller et al, 2002; Otto et al, 1997; Whiteheart et al, 2004; Yu et al, 1999; Zhao et al, 2012; Shah et al, 2015; reviewed in Sudhof and Rothman, 2009).
TRAPPC is a multi-subunit tethering complex that facilitates ER-to-Golgi traffic (reviewed in Barrowman et al, 2010; Brunet and Sacher, 2014). TRAPPC is a guanine-nucleotide exchange factor for RAB1 and is recruited to ER-derived vesicles by virtue of an interaction between the TRAPPC component TRAPPC3 and the coat protein SEC23 (Cai et al, 2007; Lord et al, 2011).
After displacement of the COPII coat, a tetrameric SNAREpin forms between the v-SNARE and the three t-SNARE proteins (Hay et al, 1997; Hay et al, 1998; Hui et al, 1997; Bentley et al, 2006; reviewed in Hong and Lev 2014). This interaction is promoted by the tethering factor USO1 and by the STX5-interacting protein SCFD1 (Wang et al, 2014; Dascher and Balch, 1996; Cao and Barlowe 2000; Flanagan and Barlowe, 2006; reviewed in Lord et al, 2013). The zippering of the SNAREpin provides the mechanical force that drives membrane fusion, releasing cargo into the acceptor compartment (reviewed in Sudhof and Rothman, 2009).
SAR1:GTP recruits the cytoplasmic SEC23:SEC24 complex. SEC24, and to a lesser extent SEC23, also mediate interaction with COPII cargo, concentrating it into the emerging vesicle. Transmembrane cargo may interact directly with the inner coat proteins, often in an isoform specific manner; alternately, some transmembrane proteins and all soluble cargo interact first with a cargo receptor of the p24, LMAN or ERV families.
Sar1p-GTP hydrolysis is increased 15-30-fold by Sec23p. Sar1p-GDP is released as a result of this hydrolysis and used in further vesicle sculpting cycles. Sar1p-GTP hydrolysis occurs at two critical points during the cycle, first (as represented here) as a proofreading step, insuring that the cargo is loaded. Later in the cycle Sar1p-GTP hydrolysis triggers the uncoating of the budded vesicle.
TBC1D20 was identified as a GTPase activating protein for RAB1 that stimulates basal GTP hydrolysis by more than 5 orders of magnitude (Haas et al, 2007; Fuchs et al, 2007).
TBC1D20 was identified as a RAB1-specific GTPase activating protein (GAP) that stimulates RAB1-mediated GTP hydrolysis and plays roles in ER-to-Golgi trafficking. TBC1D20 is the only GAP that has been identified to block delivery of secretory cargo from the ER to the cell surface (Haas et al, 2007).
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cargo
receptors:SAR1B:GTP:SEC23:SEC24Annotated Interactions
cargo
receptors:SAR1B:GTP:SEC23:SEC24cargo
receptors:SAR1B:GTP:SEC23:SEC24cargo
receptors:SAR1B:GTP:SEC23:SEC24cargo
receptors:SAR1B:GTP:SEC23:SEC24