Review
Coordination of COPII vesicle trafficking by Sec23

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Coat protein complex II (COPII) is a multi-subunit protein complex responsible for the formation of membrane vesicles at the endoplasmic reticulum. The assembly of this complex on the endoplasmic reticulum membrane needs to be tightly regulated to ensure efficient and specific incorporation of cargo proteins into nascent vesicles. Recent studies of a genetic disease affecting COPII function, and a structural analysis of COPII subunit interactions emphasize the central role of the Sec23 subunit in COPII coat assembly. Similarly, the demonstration that Sec23 interacts physically and functionally with proteins involved in both vesicle tethering and the transport along microtubules indicates that the Sec23 subunit is crucially important in linking COPII vesicle formation to anterograde transport events.

Section snippets

The COPII-coated vesicle: an introduction

The membrane-bound compartments of the secretory pathway serve to partition functions into separate micro-environments. The fact that the distinct identities of these compartments are maintained despite the continuous bi-directional traffic of transport carriers between compartments is an impressive feat. One of the ways that cells regulate the homeostatic balance is through the action of membrane coat protein complexes [1]. These protein complexes are thought to be the primary driving force

COPII coat assembly: insights from a genetic disease

Research has shown that the rare genetic disease cranio-lenticulo-sutural dysplasia (CLSD) is associated with a mutation in the SEC23A gene [19]. CLSD is characterized by malformed craniofacial structure and cataracts. The mutation results in an F382L amino acid substitution at a conserved position. Through in vitro analyses of the mutant protein, we were able to elucidate the precise effects of this disease-causing mutation [20]. The SEC23A substitution reduces the affinity of the

Recent structural studies of the COPII coat

There has been much recent progress in understanding the structural underpinnings of COPII coat formation and architecture. Using cryo-electron microscopy particle reconstruction techniques, the Balch laboratory [29] determined the beautiful structure of the assembled Sec13–Sec31 outer coat cage. Although the cuboctahedral geometry that they revealed is not quite large enough to accommodate a typical 60–70-nm COPII vesicle, it is possible that the outer coat cage can adopt different geometries,

Coat proteins provide a link to anterograde events

After COPII vesicles bud from the ER, they must be transported to and fuse with the next compartment in the secretory pathway. These events must be specifically controlled to ensure proper targeting and homeostasis. Several recent studies suggest that the COPII protein coat itself plays an important role in these events.

Post-translational modifications of COPII coat subunits

The inner coat subunits Sec23 and Sec24 are subject to post-translational modifications, providing further evidence for their importance in the regulation of COPII vesicle formation. Sec23 was ubiquitinated in yeast cells lacking the ubiquitin protease Ubp3 or the de-ubiquitinating Ubp3 co-factor Bre5 [56]. Ubiquitination of Sec23 disrupted the Sec23–Sec24 interaction and also led to proteosomal degradation. None of the other COPII subunits were ubiquitinated in ubp3Δ or bre5Δ mutant cells –

Concluding remarks and future directions

The inner layer of the COPII coat, Sar1–Sec23–Sec24 had been previously implicated in cargo sorting, but it clearly has additional roles in coordinating the completion of coat assembly, in tethering and transport to target compartments, and possibly also in regulating traffic (Figure 4). Our work on CLSD patient cells showed that the inner coat is sufficient to tubulate membranes and to select cargo in cells, but it is still not clear if the Sec23–Sec24 complex or transmembrane cargo proteins

Acknowledgements

We thank members of the Schekman laboratory for helpful discussions. J.C.F. received funding from the Miller Institute for Basic Research and the Howard Hughes Medical Institute. R.S. is funded by the Howard Hughes Medical Institute. L.O. is supported by the Swiss National Science Foundation.

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