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 MIA2 (also known as CTAGE5) interact both with the collagen cargo and with components of the COPII coat. Unlike the other cargo receptors, however, MIA3 and MIA2 are not loaded into the vesicle but remain in the ER membrane (reviewed in Malhotra and Erlmann, 2011; Malhotra et al, 2015).
View original pathway at Reactome.
Shi Y, Suh YH, Milstein AD, Isozaki K, Schmid SM, Roche KW, Nicoll RA.; ''Functional comparison of the effects of TARPs and cornichons on AMPA receptor trafficking and gating.''; 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
Kappeler F, Klopfenstein DR, Foguet M, Paccaud JP, Hauri HP.; ''The recycling of ERGIC-53 in the early secretory pathway. ERGIC-53 carries a cytosolic endoplasmic reticulum-exit determinant interacting with COPII.''; PubMedEurope PMCScholia
Jenne N, Frey K, Brugger B, Wieland FT.; ''Oligomeric state and stoichiometry of p24 proteins in the early secretory pathway.''; PubMedEurope PMCScholia
Miller E, Antonny B, Hamamoto S, Schekman R.; ''Cargo selection into COPII vesicles is driven by the Sec24p subunit.''; PubMedEurope PMCScholia
Kamiya Y, Kamiya D, Yamamoto K, Nyfeler B, Hauri HP, Kato K.; ''Molecular basis of sugar recognition by the human L-type lectins ERGIC-53, VIPL, and VIP36.''; PubMedEurope PMCScholia
Malhotra V, Erlmann P.; ''Protein export at the ER: loading big collagens into COPII carriers.''; PubMedEurope PMCScholia
Castro CP, Piscopo D, Nakagawa T, Derynck R.; ''Cornichon regulates transport and secretion of TGFalpha-related proteins in metazoan cells.''; PubMedEurope PMCScholia
Appenzeller C, Andersson H, Kappeler F, Hauri HP.; ''The lectin ERGIC-53 is a cargo transport receptor for glycoproteins.''; PubMedEurope PMCScholia
Nyfeler B, Reiterer V, Wendeler MW, Stefan E, Zhang B, Michnick SW, Hauri HP.; ''Identification of ERGIC-53 as an intracellular transport receptor of alpha1-antitrypsin.''; PubMedEurope PMCScholia
Hammond AT, Glick BS.; ''Dynamics of transitional endoplasmic reticulum sites in vertebrate cells.''; PubMedEurope PMCScholia
Strating JR, Martens GJ.; ''The p24 family and selective transport processes at the ER-Golgi interface.''; PubMedEurope PMCScholia
Malhotra V, Erlmann P, Nogueira C.; ''Procollagen export from the endoplasmic reticulum.''; PubMedEurope PMCScholia
Mancias JD, Goldberg J.; ''The transport signal on Sec22 for packaging into COPII-coated vesicles is a conformational epitope.''; PubMedEurope PMCScholia
Saito K, Yamashiro K, Ichikawa Y, Erlmann P, Kontani K, Malhotra V, Katada T.; ''cTAGE5 mediates collagen secretion through interaction with TANGO1 at endoplasmic reticulum exit sites.''; 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
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
Schwenk J, Harmel N, Zolles G, Bildl W, Kulik A, Heimrich B, Chisaka O, Jonas P, Schulte U, Fakler B, Klöcker N.; ''Functional proteomics identify cornichon proteins as auxiliary subunits of AMPA receptors.''; PubMedEurope PMCScholia
Bonnon C, Wendeler MW, Paccaud JP, Hauri HP.; ''Selective export of human GPI-anchored proteins from the endoplasmic reticulum.''; PubMedEurope PMCScholia
Mossessova E, Bickford LC, Goldberg J.; ''SNARE selectivity of the COPII coat.''; PubMedEurope PMCScholia
Kamiya Y, Yamaguchi Y, Takahashi N, Arata Y, Kasai K, Ihara Y, Matsuo I, Ito Y, Yamamoto K, Kato K.; ''Sugar-binding properties of VIP36, an intracellular animal lectin operating as a cargo receptor.''; PubMedEurope PMCScholia
Reiterer V, Nyfeler B, Hauri HP.; ''Role of the lectin VIP36 in post-ER quality control of human alpha1-antitrypsin.''; PubMedEurope PMCScholia
Dominguez M, Dejgaard K, Füllekrug J, Dahan S, Fazel A, Paccaud JP, Thomas DY, Bergeron JJ, Nilsson T.; ''gp25L/emp24/p24 protein family members of the cis-Golgi network bind both COP I and II coatomer.''; PubMedEurope PMCScholia
Mitrovic S, Ben-Tekaya H, Koegler E, Gruenberg J, Hauri HP.; ''The cargo receptors Surf4, endoplasmic reticulum-Golgi intermediate compartment (ERGIC)-53, and p25 are required to maintain the architecture of ERGIC and Golgi.''; PubMedEurope PMCScholia
Szul T, Sztul E.; ''COPII and COPI traffic at the ER-Golgi interface.''; PubMedEurope PMCScholia
Dancourt J, Barlowe C.; ''Protein sorting receptors in the early secretory pathway.''; 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
Nyfeler B, Zhang B, Ginsburg D, Kaufman RJ, Hauri HP.; ''Cargo selectivity of the ERGIC-53/MCFD2 transport receptor complex.''; PubMedEurope PMCScholia
Hauri HP, Kappeler F, Andersson H, Appenzeller C.; ''ERGIC-53 and traffic in the secretory pathway.''; PubMedEurope PMCScholia
Mancias JD, Goldberg J.; ''Structural basis of cargo membrane protein discrimination by the human COPII coat machinery.''; 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
Zheng C, Zhang B.; ''Combined deficiency of coagulation factors V and VIII: an update.''; PubMedEurope PMCScholia
Sato K, Nakano A.; ''Mechanisms of COPII vesicle formation and protein sorting.''; PubMedEurope PMCScholia
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.
TMED2 and TMED10 are members of the p24 family of proteins that bind GPI anchored proteins in the ER and mediate their incorporation into COPII vesicles (Bonnon et al, 2010; reviewed in Strating et al, 2009). p24 proteins function as heteromeric complexes and interact with components of the COPII coat (Jenne et al, 2002; Dominguez et al, 1998; reviewed in Strating et al, 2009). In complex with LMAN1 and SURF4, they also play a role in maintaining the structure of the ERGIC (Mitrovic et al, 2008).
SEC24 isoforms C and D are required in conjunction with SEC23A for packaging the t-SNARES STX5 and GOSR2 into COPII vesicles for transport to the Golgi (Mancias and Goldberg, 2008).
Of the four human SEC24 isoforms, SEC24A and B are required for packaging the v-SNARE SEC22 into COPII vesicles. Recognition of the ER packaging epitope on SEC22 also depends on SEC23A (Mancias and Goldberg, 2007).
Procollagen VII trimers, which are too large for standard COPII vesicles, are packaged into larger transport vesicles through interaction with the transmembrane accessory proteins MIA3 (also known as TANGO1) and MIA2 (also known as CTAGE5). MIA3 interacts with collagen through its lumenal SH3 domain and interacts with SEC23 and SEC24 through the proline rich domain (Saito et al, 2009; reviewed in Malhotra and Erlmann, 2011; Malhotra et al, 2015).
LMAN1, also known as ERGIC-53, is a transmembrane receptor that binds to high-mannose containing soluble glycoproteins in the ER and helps package them into COPII vesicles for trafficking to the ERGIC and Golgi. Identified cargo include SERPINA (alpha1-antitrypsin) and the cathepsins CTSC and CTSZ, among others (Nyefeler et al, 2008; Appenzeller et al, 1999; reviewed in Hauri et al, 2000; Szul and Sztul, 2011). LMAN1 itself is concentrated into COPII vesicles through interaction with components of the COPII coat (Kappeler et al, 1997; reviewed in Dancourt and Barlowe, 2010). Other LMAN family proteins, which include LMANL1, LMAN2 and LMAN2L, also bind glycosylated ER cargo proteins, although the lectin specificities vary (Kamiya et al, 2005; Kamiya et al, 2007; Reiterer et al, 2010; reviewed in Dancourt and Barlowe, 2010).
Secretion of the clotting factor precursors Factor V and Factor VIII from the ER depends on interaction with a Ca2+-dependent receptor complex of LMAN1 and its soluble interaction partner MCFD2 (Nyfeler et al, 2006; reviewed in Zheng and Zhang, 2013; Dancourt and Barlowe, 2010).
MIA2 (also known as CTAGE5), a transmembrane ER protein with roles in collagen secretion, recruits the SAR1 GEF PREB (also known as SEC12) to ER exit sites (Saito et al, 2014).
MIA2 (also known as CTAGE5) and MIA3 form heterodimers through their second coiled coil domains and interact with inner coat proteins SEC24C and SEC23A through their proline-rich domains. In this way, the MIA3 and MIA2 concentrate procollagen VII at ER exit sites (Saito et al, 2011; reviewed in Malhotra and Erlmann, 2011; Malhotra et al, 2015).
Unlike other cargo receptors, MIA2 (also known as CTAGE5) and MIA3 are not packaged into COPII vesicles but remain behind in the ER membrane. Dissociation of MIA3 from procollagen and from inner coat proteins SEC23 and SEC24 is thought to trigger recruitment of the outer coat proteins SEC13/31, allowing COPII coat maturation (Saito et al, 2009; Saito et al, 2011; reviewed in Malhotra and Erlmann, 2011; Malhotra et al, 2015).
CNIH2 and 3 are members of the ERV14 family of transmembrane proteins with a role in chaperoning cargo out of the ER (reviewed in Dancourt and Barlowe, 2010). CNIH2 and 3 bind to components of the AMPA-type glutamate receptor complex, including GRIA1 in the ER and facilitate their trafficking to the plasma membrane. CNIH2 and 3 may play additional roles at the cell surface modulating the function of the channels (Shi et al, 2010; Schwenk et al, 2009).
CNIH1, also known as ERV14, is a member of the ERV family of proteins that act as cargo receptors for ER-to-ERGIC trafficking (reviewed in Dancourt and Barlowe, 2010). CNIH1 preferentially interacts with transmembrane proteins like the precursor forms of TFGA and AREG, and mediates their packaging into COPII vesicles by interacting with components of the COPII coat (Castro et al, 2007).
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.
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cargo
receptors:SAR1B:GTP:SEC23:SEC24tetramer:GPI-CD59,
GPI-FOLR1Annotated Interactions
cargo
receptors:SAR1B:GTP:SEC23:SEC24tetramer:GPI-CD59,
GPI-FOLR1