Sorting and Export of Proteins at the Endoplasmic Reticulum

Abstract

Secretory proteins are transported from the endoplasmic reticulum (ER) to the Golgi complex in carriers that are formed by the concerted activities of cytoplasmic proteins in the coat protein complex II (COPII). COPII was first described in Saccharomyces cerevisiae and its basic functions are largely conserved throughout eukaryotes. The discovery of the TANGO1 (transport and Golgi organization 1) family of proteins is revealing insights into how cells can adapt COPII proteins to reorganize the ER exit site for the export of the most abundant and bulky molecules, collagens.

Figure 1.

The secretory pathway. A schema based on a foundation laid by George Palade's classical electron microscopic characterization of the cellular secretory pathway. Secretory proteins are synthesized and folded in the endoplasmic reticulum (ER). They then gather at specialized subdomains of the ER called ER exit sites, marked by coat protein complex II (COPII) proteins. In the conventional model, proteins are packaged into COPII-coated vesicles, which detach from the ER and fuse with the next compartment, the ERGIC (ER-Golgi intermediate compartment) and thence on through the Golgi apparatus to their final destination. Materials that need to be retrieved are packaged into a similar class of vesicles called COPI-coated vesicles for their retrograde transport to the ER.

Figure 2.

Coat protein complex II (COPII)-coated vesicle biogenesis. Cytosolic machinery assembles in a hierarchical manner at an endoplasmic reticulum (ER) exit site (ERES). The small GTPase Sar1 is recruited to the ER membrane. This in turn recruits an inner COPII coat of Sec23/Sec24. Secretory cargo in the ER binds to cargo receptors, which bind to Sec24. The Sar1-Sec23/24 “prebudding” complex recruits an outer COPII coat of Sec13/31 that sculpts the site into a vesicle. The vesicle buds off of the ER and forms a 60-nm coated vesicle. Vesicle uncoating exposes machinery required for vesicle targeting and fusion to a downstream compartment.

Figure 3.

The transport and Golgi organization 1 (TANGO1) family of proteins. Mammalian TANGO1 family of proteins. Full-length TANGO1 or TANGO1-like (TALI) consists of an endoplasmic reticulum (ER)-lumenal part, with extensive regions that are predicted to be intrinsically disordered and an SH3-like domain. The cytoplasmic face of the ER membrane contains coiled coils (CC1 and CC2) and a carboxy-terminal proline-rich domain (PRD). Secreted isoforms MIA and otoraplin are almost exclusively an SH3-like domain. Other paralogs and their isoforms include TANGO1-Short, cTAGE5, and several predicted cTAGEx proteins (where x is 2, 4, 6, 8, 9, and 15). Each domain interacts with a specific set of proteins as indicated.

Figure 4.

TANGO1 (transport and Golgi organization 1) stabilizes a transient tunnel between the endoplasmic reticulum (ER) and the ER-Golgi intermediate compartment (ERGIC). TANGO1 at the base of nascent bud, binds to multiple Sec23/24 and promotes a cylindrical coat protein complex II (COPII) assembly. Via the NRZ tether, TANGO1 holds the ERGIC (pink membranes) in place at the ER exit sites (ERES). This could result in a transient continuity generated between the ER (blue) and the ERGIC (pink).