COPII - a flexible vesicle formation system

Abstract

Long known as a coat system that generates small transport vesicles from the endoplasmic reticulum (ER), the COPII coat also drives ER export of cargo proteins that are too large to be contained within these canonical carriers. With crystal and cryo-EM structures giving an atomic level view of coat architecture, current advances in the field have focused on understanding how the coat adapts to the different geometries of the underlying cargo. Combined with a growing appreciation for the specific roles of individual COPII paralogs in diverse aspects of mammalian physiology, the field is poised to understand how coat assembly and post-translational modification permits structural rigidity but geometric flexibility to handle the diverse cargoes that exit the ER.

Figure 1. Structure and assembly of the COPII coat

The guanine nucleotide exchange factor, Sec12 (4H5I [8]) catalyzes GTP loading on Sar1, which switches from a cytosolic GDP-bound form (1F6B [59]) to a membrane-associated GTP-bound form (1M2O [6]) through exposure of an N-terminal amphipathic -helix. Membrane-associated Sar1 recruits Sec23/Sec24 (1M2V [6]). Sec24 provides cargo-binding function by directly interacting with sorting signals on transmembrane clients. The Sar1/Sec23/Sec24 “pre-budding” complex in turn recruits Sec13/Sec31 (2PM6 and 2PM9 [7]). Sec13/Sec31 self-assembles into a polyhedral cage (inset, adapted by permission from Macmillan Pulishers Ltd: Nature [9], copyright 2006) that at least in part drives membrane curvature and contributes to vesicle scission. Sec23 is the GTPase-activating protein for Sar1, with Sec31 further contributing to hydrolysis via a proline-rich domain that extends across the surface of Sec23/Sar1. Sec16 is a peripheral component that binds to Sec13 (3MZK [40]), modulates GTPase activity by preventing Sec31 action and otherwise contributes to vesicle formation in poorly understood ways.

Figure 2. Flexible form and function of COPII vesicles

The canonical COPII vesicles, as initially characterized in yeast, is 60–80nm in diameter and forms through the action of the minimal COPII coat, Sar1/Sec23/Sec24/Sec13/Sec31, on both complex ER membranes and synthetic liposomes. Different cargo molecules dictate distinct requirements for the size and shape of vesicles. Although the precise mechanisms by which these distinct morphologies are created, in many cases they require either specific COPII paralogs (noted in red) or additional cargo adaptors. In yeast, GPI-anchored proteins (GPI-APs) and the multimeric Pma1 complex depend on the Sec24 paralog, Lst1/Sfb2, for efficient capture into vesicles that are markedly larger than standard COPII vesicles. Pro-collagen assembles into long rods that are too long for a standard vesicle and are likely packaged into a more tubular structure, although these carriers have not been directly visualized. Efficient ER export of pro-collagen relies on the putative adaptor protein, TANGO-1, and is sensitive to mutations in SEC23B and knock-down of SEC13. Pre-chylomicrons are large lipid particles that accumulate in the ER when SAR1B is mutated.