1. The Genetic Basis of a Craniofacial Disease Provides Insight into COPII Coat Assembly
- Author
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Randy Schekman, Mohammed Al-Balwi, Mariella Ravazzola, Lelio Orci, Wafaa Eyaid, Susan Hamamoto, Simeon A. Boyadjiev, Pierre Cosson, and J. Christopher Fromme
- Subjects
Models, Molecular ,Membrane coat ,Molecular Sequence Data ,Vesicular Transport Proteins ,HUMDISEASE ,Carrier Proteins/metabolism ,Vesicular Transport Proteins/genetics/metabolism ,Biology ,Endoplasmic Reticulum ,Craniofacial Abnormalities/genetics/metabolism/pathology ,Membrane Fusion ,Article ,General Biochemistry, Genetics and Molecular Biology ,Craniofacial Abnormalities ,Osteoblasts/physiology ,Membrane fission ,Fibroblasts/physiology ,Endoplasmic Reticulum/physiology ,Humans ,Amino Acid Sequence ,ddc:612 ,Molecular Biology ,COPII ,Cells, Cultured ,Secretory pathway ,Monomeric GTP-Binding Proteins ,Osteoblasts ,Monomeric GTP-Binding Proteins/metabolism ,Cell Membrane/metabolism ,Cell Membrane ,Cell Biology ,COPI ,Fibroblasts ,SEC23A ,COP-Coated Vesicles ,Cell biology ,Protein Transport ,SEC31 ,Mutation ,COP-Coated Vesicles/physiology ,CELLBIO ,Carrier Proteins ,Developmental Biology - Abstract
SummaryProteins trafficking through the secretory pathway must first exit the endoplasmic reticulum (ER) through membrane vesicles created and regulated by the COPII coat protein complex. Cranio-lenticulo-sutural dysplasia (CLSD) was recently shown to be caused by a missense mutation in SEC23A, a gene encoding one of two paralogous COPII coat proteins. We now elucidate the molecular mechanism underlying this disease. In vitro assays reveal that the mutant form of SEC23A poorly recruits the Sec13-Sec31 complex, inhibiting vesicle formation. Surprisingly, this effect is modulated by the Sar1 GTPase paralog used in the reaction, indicating distinct affinities of the two human Sar1 paralogs for the Sec13-Sec31 complex. Patient cells accumulate numerous tubular cargo-containing ER exit sites devoid of observable membrane coat, likely representing an intermediate step in COPII vesicle formation. Our results indicate that the Sar1-Sec23-Sec24 prebudding complex is sufficient to form cargo-containing tubules in vivo, whereas the Sec13-Sec31 complex is required for membrane fission.
- Published
- 2007
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