8e0d
Crystal structure of human Sar1bE140D
Structural highlights
DiseaseSAR1B_HUMAN Chylomicron retention disease. The disease is caused by variants affecting the gene represented in this entry. FunctionSAR1B_HUMAN GTP-binding protein involved in transport from the endoplasmic reticulum to the Golgi apparatus (By similarity). Activated by the guanine nucleotide exchange factor PREB (By similarity). Involved in the selection of the protein cargo and the assembly of the COPII coat complex (By similarity). Synergizes with the cargo receptor SURF4 to mediate the export of lipoproteins from the endoplasmic reticulum, thereby regulating lipoprotein delivery and the maintenance of lipid homeostasis (PubMed:33186557).[UniProtKB:Q9QVY3][1] Publication Abstract from PubMedTransport of newly synthesized proteins from endoplasmic reticulum (ER) to Golgi is mediated by coat protein complex II (COPII). The assembly and disassembly of COPII vesicles is regulated by the molecular switch Sar1, which is a small GTPase and a component of COPII. Usually a small GTPase binds GDP (inactive form) or GTP (active form). Mammals have two Sar1 isoforms, Sar1a and Sar1b, that have approximately 90% sequence identity. Some experiments demonstrated that these two isoforms had distinct but overlapping functions. Here we found another instance of differing behavior: the alarmone ppGpp could bind to and inhibit the GTPase activity of human Sar1a but could not inhibit the GTPase activity of human Sar1b. The crystal structures of Sar1aâ ppGpp and Sar1bâ GDP have been determined. Superposition of the structures shows that ppGpp binds to the nucleotide-binding pocket, its guanosine base, ribose ring and 5'-diphosphate occupying nearly the same positions as for GDP. However, its 3'-diphosphate points away from the active site and, hence, away from the surface of the protein. The overall structure of Sar1aâ ppGpp is more similar to Sar1bâ GDP than to Sar1bâ GTP. We also find that the Asp140-Arg138-water-ligand interaction net is important for the binding of ppGpp to Sar1a. This study provides further evidence showing that there are biochemical differences between the Sar1a and Sar1b isoforms of Sar1. The alarmone ppGpp selectively inhibits the isoform A of the human small GTPase Sar1.,Huang Q, Szebenyi DME Proteins. 2022 Nov 11. doi: 10.1002/prot.26445. PMID:36369712[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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