6LCY

Crystal structure of Synaptotagmin-7 C2B in complex with IP6

Summary for 6LCY

• Entry DOI: 10.2210/pdb6lcy/pdb
• Descriptor: Synaptotagmin-7, INOSITOL HEXAKISPHOSPHATE (3 entities in total)
• Functional Keywords: synaptotagmin-7, ip6, insulin secretion, exocytosis
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 1
• Total formula weight: 17775.28

Authors

Zhang, Y.,Zhang, X.,Rao, F.,Wang, C. (deposition date: 2019-11-20, release date: 2021-03-03, Last modification date: 2023-11-22)

Primary citation

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.
5-IP 7 is a GPCR messenger mediating neural control of synaptotagmin-dependent insulin exocytosis and glucose homeostasis.
Nat Metab, 3:1400-1414, 2021

PubMed Abstract: 5-diphosphoinositol pentakisphosphate (5-IP) is a signalling metabolite linked to various cellular processes. How extracellular stimuli elicit 5-IP signalling remains unclear. Here we show that 5-IP in β cells mediates parasympathetic stimulation of synaptotagmin-7 (Syt7)-dependent insulin release. Mechanistically, vagal stimulation and activation of muscarinic acetylcholine receptors triggers G-PLC-PKC-PKD-dependent signalling and activates IP6K1, the 5-IP synthase. Whereas both 5-IP and its precursor IP compete with PIP for binding to Syt7, Ca selectively binds 5-IP with high affinity, freeing Syt7 to enable fusion of insulin-containing vesicles with the cell membrane. β-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-IP acts as a GPCR second messenger at the interface between peripheral nervous system and metabolic organs, transmitting G-coupled GPCR stimulation to unclamp Syt7-dependent, and perhaps other, exocytotic events.

PubMed: 34663975
DOI: 10.1038/s42255-021-00468-7

Experimental method

X-RAY DIFFRACTION (2.301 Å)