Signals for COPII-dependent export from the ER: what's the ticket out?

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Abstract

Export of many secretory proteins from the endoplasmic reticulum (ER) relies on signal-mediated sorting into ER-derived transport vesicles. Recent work on the coat protein complex II (COPII) provides new insight into the mechanisms and signals that govern this selective export process. Conserved di-acidic and di-hydrophobic motifs found in specific transmembrane cargo proteins are required for their selection into COPII-coated vesicles. These signaling elements are cytoplasmically exposed and recognized by subunits of the COPII coat. Certain soluble cargo molecules depend on receptor-like proteins for efficient ER export, although signals that direct soluble cargo into ER-derived vesicles are less defined.

Section snippets

Overview of the early secretory pathway

The coat protein complex II (COPII) forms transport vesicles from the ER and collects the appropriate cargo proteins into these vesicles. Certain signals have been implicated in COPII-dependent export; however, there is an extraordinary diversity in the cargo selected by the COPII coat and many exported proteins do not contain known sorting signals. Moreover, the ER export machinery has to deal with an additional complexity, introduced by the process of quality control, whereby export cargo is

Assembly of the COPII coat

The COPII coat consists of three proteins (Sar1, Sec23–Sec24 complex and Sec13–Sec31 complex) that are sequentially recruited to the ER membrane surface (Fig. 2). Sar1 is a small 21-kDa GTPase, whereas Sec23–Sec24 and Sec13–Sec31 are large heteromeric protein complexes. The Sar1 GTPase cycle is thought to regulate coat assembly and disassembly. To assemble the COPII coat, membrane-bound Sar1–GTP binds to Sec23–Sec24 that in turn attracts Sec13–Sec31 [5]. Activation of Sar1 to Sar1–GTP is

The COPII coat selects export cargo into ER-derived transport vesicles

Experimental evidence demonstrates that certain cargo, in order to be included into COPII vesicles, possess a binding affinity for subunits of the coat. More specifically, pre-budding complexes consisting of Sar1–GTP and Sec23–Sec24 bound to cargo can be isolated under conditions that preserve the Sar–GTP-bound configuration 11, 12. Based on these findings, a model integrating cargo selection and COPII vesicle formation can be constructed as shown in Fig. 2. In this model, pre-budding complexes

ER export signals

Based on these findings, it has been hypothesized that ER-export cargo possesses surface residues or sequence motifs that are bound to Sar1–Sec23–Sec24 pre-budding complexes directly or indirectly 11, 12. What are these signals and how are they recognized? Recent studies have identified specific signals on transmembrane cargo to support this hypothesis, and structural studies are closing in on precise contacts between cargo and coat. For soluble secretory cargo proteins that cannot be bound

Signals in transmembrane cargo

Transport of the vesicular stomatitis virus glycoprotein (VSV-G) has served as a model for study of secretory protein folding and export from the ER. VSV-G, a type I transmembrane protein that traffics to the cell surface, is abundantly expressed in VSV-infected cells and concentrated into ER-derived transport vesicles 14, 15. VSV-G possesses a cytoplasmically exposed C-terminal tail sequence of 29 residues that is required for transport from the ER. Within this tail sequence, a conserved YTDIE

Sec24 proteins ‘collect the tickets’

Several lines of evidence indicate that a family of Sec24 proteins functions in cargo recognition. Furthermore, the presence of multiple Sec24 homologs appears to expand the variety of cargo that must be efficiently exported from the ER. Yeast cells express two additional Sec24-like proteins, termed Lst1 and Iss1. Higher eukaryotes are endowed with at least four Sec24 isoforms [28]. In yeast, the Lst1 subunit is not essential for COPII-dependent export but is required for efficient export of

Export signals in soluble secretory cargo

Up to this point, the export signals considered have focused on transmembrane cargo proteins, which are directly accessible to COPII subunits. However, there are a variety of soluble secretory proteins that are efficiently exported from the ER and cannot directly contact the COPII coat. Two non-exclusive models, known as the ‘bulk flow’ and ‘receptor-mediated’ export models, have been described in studies addressing export of soluble cargo from the ER (Fig. 3).

First, a passive or ‘bulk flow’

Concluding remarks

Specific amino acid sequence motifs in transmembrane cargo molecules have been identified that are required for concentrative sorting into ER-derived vesicles. Both the di-acidic and di-hydrophobic motifs in export cargo bind to subunits of the COPII coat, providing a direct mechanism for cargo selection. The Sec23–Sec24 protein complex serves a role in cargo recognition, whereas the Sar1 GTPase appears to regulate interactions between coat and cargo. Structural studies on coat–cargo complexes

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