SAR1 paralogs differ biochemically in assembly of the COPII coat

Abstract

COPII-coated vesicles are the primary mediators of vesicular traffic from the ER to the Golgi apparatus. SAR1 is a small GTPase, which, upon GTP binding, recruits the other COPII proteins to the ER membrane. In mammals, there are two SAR1 paralogs which genetic data suggest may have distinct physiological roles, e.g. in lipoprotein secretion for SAR1B. We identified two clusters of amino acids that have conserved, paralog-specific sequences. One cluster is adjacent to the SAR1 GTP-binding pocket and alters the kinetics of GTP exchange. The other cluster is adjacent to the binding site of COPII components SEC31 and SEC23. We found that the latter cluster confers a SEC23A binding preference to SAR1B over SAR1A. In contrast to SAR1B, SAR1A is prone to oligomerize on a membrane surface. Importantly, in relation to its physiological function, SAR1B, but not SAR1A, can compensate for loss of SAR1B in lipoprotein secretion. The SEC31/SEC23-binding siteadjacent divergent cluster is critical for this function. These data identify the novel paralogspecific function for SAR1B, and provide insights into the mechanisms of large cargo secretion and COPII related diseases.

A Creb3-Like Transcription Factor Coordinates ER Function upon Food Intake to Regulate Lipid Metabolism

“…Absence of MTP in humans and flies results in the absence of circulating ApoB (Aggerbeck et al, 1992) and Apolpp/Apoltp, respectively (Palm et al, 2012). For further maturation, these particles exit the ER and are transported to the Golgi via specialized COPII vesicles which carry large cargos (Santos et al, 2016;Siddiqi et al, 2018;Melville et al, 2020). Importantly, interfering with this process prevents lipid transport from the liver and results in hepatosteatosis and hypobetalipoproteinemia (Zhong et al, 2010;Burnett et al, 2007;Burnett et al, 2003;Minehira et al, 2008).…”