6lcy

Crystal structure of Synaptotagmin-7 C2B in complex with IP6

spinqualitylabelsall models 6lcy, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6lcy is a 1 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.301Å Ligands: IHP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function SYT7_MOUSE May be involved in Ca(2+)-dependent exocytosis of secretory vesicles through Ca(2+) and phospholipid binding to the C2 domain or may serve as Ca(2+) sensors in the process of vesicular trafficking and exocytosis (By similarity). Publication Abstract from PubMed 5-diphosphoinositol pentakisphosphate (5-IP7) is a signalling metabolite linked to various cellular processes. How extracellular stimuli elicit 5-IP7 signalling remains unclear. Here we show that 5-IP7 in beta cells mediates parasympathetic stimulation of synaptotagmin-7 (Syt7)-dependent insulin release. Mechanistically, vagal stimulation and activation of muscarinic acetylcholine receptors triggers Galphaq-PLC-PKC-PKD-dependent signalling and activates IP6K1, the 5-IP7 synthase. Whereas both 5-IP7 and its precursor IP6 compete with PIP2 for binding to Syt7, Ca(2+) selectively binds 5-IP7 with high affinity, freeing Syt7 to enable fusion of insulin-containing vesicles with the cell membrane. beta-cell-specific IP6K1 deletion diminishes insulin secretion and glucose clearance elicited by muscarinic stimulation, whereas mice carrying a phosphorylation-mimicking, hyperactive IP6K1 mutant display augmented insulin release, congenital hyperinsulinaemia and obesity. These phenotypes are absent in mice lacking Syt7. Our study proposes a new conceptual framework for inositol pyrophosphate physiology in which 5-IP7 acts as a GPCR second messenger at the interface between peripheral nervous system and metabolic organs, transmitting Gq-coupled GPCR stimulation to unclamp Syt7-dependent, and perhaps other, exocytotic events. 5-IP7 is a GPCR messenger mediating neural control of synaptotagmin-dependent insulin exocytosis and glucose homeostasis.,Zhang X, Li N, Zhang J, Zhang Y, Yang X, Luo Y, Zhang B, Xu Z, Zhu Z, Yang X, Yan Y, Lin B, Wang S, Chen D, Ye C, Ding Y, Lou M, Wu Q, Hou Z, Zhang K, Liang Z, Wei A, Wang B, Wang C, Jiang N, Zhang W, Xiao G, Ma C, Ren Y, Qi X, Han W, Wang C, Rao F Nat Metab. 2021 Oct;3(10):1400-1414. doi: 10.1038/s42255-021-00468-7. Epub 2021, Oct 18. PMID:34663975 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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