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      Regulation of the Sar1 GTPase Cycle Is Necessary for Large Cargo Secretion from the Endoplasmic Reticulum

      review-article
      , ,
      Frontiers in Cell and Developmental Biology
      Frontiers Media S.A.
      SAR1, Sec12, COPII, ER, collagen, cTAGE5, Tango1, Sec16

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          Abstract

          Proteins synthesized within the endoplasmic reticulum (ER) are transported to the Golgi via coat protein complex II (COPII)-coated vesicles. The formation of COPII-coated vesicles is regulated by the GTPase cycle of Sar1. Activated Sar1 is recruited to ER membranes and forms a pre-budding complex with cargoes and the inner-coat complex. The outer-coat complex then stimulates Sar1 inactivation and completes vesicle formation. The mechanisms of forming transport carriers are well-conserved among species; however, in mammalian cells, several cargo molecules such as collagen, and chylomicrons are too large to be accommodated in conventional COPII-coated vesicles. Thus, special cargo-receptor complexes are required for their export from the ER. cTAGE5/TANGO1 complexes and their isoforms have been identified as cargo receptors for these macromolecules. Recent reports suggest that the cTAGE5/TANGO1 complex interacts with the GEF and the GAP of Sar1 and tightly regulates its GTPase cycle to accomplish large cargo secretion.

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          Most cited references90

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          COPII: a membrane coat formed by Sec proteins that drive vesicle budding from the endoplasmic reticulum.

          In vitro synthesis of endoplasmic reticulum-derived transport vesicles has been reconstituted with washed membranes and three soluble proteins (Sar1p, Sec13p complex, and Sec23p complex). Vesicle formation requires GTP but can be driven by nonhydrolyzable analogs such as GMP-PNP. However, GMP-PNP vesicles fail to target and fuse with the Golgi complex whereas GTP vesicles are functional. All the cytosolic proteins required for vesicle formation are retained on GMP-PNP vesicles, while Sar1p dissociates from GTP vesicles. Thin section electron microscopy of purified preparations reveals a uniform population of 60-65 nm vesicles with a 10 nm thick electron dense coat. The subunits of this novel coat complex are molecularly distinct from the constituents of the nonclathrin coatomer involved in intra-Golgi transport. Because the overall cycle of budding driven by these two types of coats appears mechanistically similar, we propose that the coat structures be called COPI and COPII.
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            Intracellular aspects of the process of protein synthesis.

            G E Palade (1975)
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              Sar1p N-terminal helix initiates membrane curvature and completes the fission of a COPII vesicle.

              Secretory proteins traffic from the ER to the Golgi via COPII-coated transport vesicles. The five core COPII proteins (Sar1p, Sec23/24p, and Sec13/31p) act in concert to capture cargo proteins and sculpt the ER membrane into vesicles of defined geometry. The molecular details of how the coat proteins deform the lipid bilayer into vesicles are not known. Here we show that the small GTPase Sar1p directly initiates membrane curvature during vesicle biogenesis. Upon GTP binding by Sar1p, membrane insertion of the N-terminal amphipathic alpha helix deforms synthetic liposomes into narrow tubules. Replacement of bulky hydrophobic residues in the alpha helix with alanine yields Sar1p mutants that are unable to generate highly curved membranes and are defective in vesicle formation from native ER membranes despite normal recruitment of coat and cargo proteins. Thus, the initiation of vesicle budding by Sar1p couples the generation of membrane curvature with coat-protein assembly and cargo capture.
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                Author and article information

                Contributors
                Journal
                Front Cell Dev Biol
                Front Cell Dev Biol
                Front. Cell Dev. Biol.
                Frontiers in Cell and Developmental Biology
                Frontiers Media S.A.
                2296-634X
                23 August 2017
                2017
                : 5
                : 75
                Affiliations
                Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo Tokyo, Japan
                Author notes

                Edited by: J. Christopher Fromme, Cornell University, United States

                Reviewed by: Anjon Audhya, University of Wisconsin-Madison, United States; Geri Kreitzer, CUNY School of Medicine, United States

                *Correspondence: Kota Saito ksaito@ 123456mol.f.u-tokyo.ac.jp

                This article was submitted to Membrane Traffic, a section of the journal Frontiers in Cell and Developmental Biology

                †Present Address: Toshiaki Katada, Faculty of Pharmacy, Musashino University, Tokyo, Japan

                Article
                10.3389/fcell.2017.00075
                5572378
                28879181
                84fe8768-a6b1-4090-bab2-38e277cb8ac6
                Copyright © 2017 Saito, Maeda and Katada.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 26 June 2017
                : 10 August 2017
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 96, Pages: 8, Words: 6972
                Funding
                Funded by: Japan Society for the Promotion of Science 10.13039/501100001691
                Categories
                Cell and Developmental Biology
                Mini Review

                sar1,sec12,copii,er,collagen,ctage5,tango1,sec16
                sar1, sec12, copii, er, collagen, ctage5, tango1, sec16

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