期刊
DEVELOPMENTAL CELL
卷 13, 期 5, 页码 623-634出版社
CELL PRESS
DOI: 10.1016/j.devcel.2007.10.005
关键词
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资金
- Howard Hughes Medical Institute Funding Source: Medline
- NCRR NIH HHS [M01 RR000052, M01-RR00052] Funding Source: Medline
- NIDCR NIH HHS [R01 DE016886, K23 DE000462, K23 DE00462, R03 DE016342, R03 DE16342] Funding Source: Medline
- NIGMS NIH HHS [R01 GM026755, R01 GM026755-25] Funding Source: Medline
Proteins trafficking through the secretory pathway must first exit the endoplasmic reticulum (ER) through membrane vesicles created and regulated by the COPll 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 CON 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 COPll 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.
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