SCGN-regulated Stage-wise SNARE Assembly: Novel Insight into Synaptic Exocytosis
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RESEARCH HIGHLIGHT
SCGN-regulated Stage-wise SNARE Assembly: Novel Insight into Synaptic Exocytosis Ying Lv1 • Sunmin Xiang2 • Renxian Cao2 • Li Wu2 • Jing Yang2
Received: 21 June 2020 / Accepted: 19 July 2020 Ó Shanghai Institutes for Biological Sciences, CAS 2020
In neuroendocrine cells, hormones and neuropeptides stored in secretory granules are released in response to various stimuli in a highly concerted process, including the sequential actions of vesicle trafficking, docking, fusion, and unloading. In this process, the crucial step of vesicle fusion requires the formation of a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, comprising primarily SNAP-25, syntaxin 1, and synaptobrevin 2 [1, 2]. After synaptic exocytosis, the SNARE complex is disassembled for another round of fusion, and the assembly and recycling of SNARE complex components are orchestrated by a cascade of regulators, including N-ethylmaleimide-sensitive factor (NSF), soluble NSF adaptor proteins (SNAPs), Munc18-1, Munc13-1, and others [1, 3]. NSF and the SNAPs disassemble the SNARE complex to recycle SNARE components for subsequent rounds of fusion, whereas Munc18-1 and Munc13-1 facilitate SNARE complex assembly in an NSF-SNAP-resistant manner [3, 4]. In addition to these well-recognized regulators, several proteins that chaperone components for SNARE complex formation remain to be discovered. Secretagogin (SCGN), an EF-hand Ca2?-sensor hexamer protein expressed mainly in pancreatic islets, brain Ying Lv and Sunmin Xiang have contributed equally to this work. & Jing Yang [email protected] 1
Department of Metabolism and Endocrinology, The Second Affiliated Hospital of the University of South China, Hengyang 421001, China
2
Department of Metabolism and Endocrinology, The First Affiliated Hospital of the University of South China, Hengyang 421001, China
cells, and gastrointestinal endocrine cells, has recently been identified as a crucial player in the regulation of exocytosis [5]. Studies have shown that the secretion of insulin, corticotropin-releasing hormone, glucagon-like peptide-1 (GLP-1), and matrix metalloprotease-2 is regulated by SCGN [5–7]. It is generally accepted that SCGN modulates hormone exocytosis by interacting with cytoskeletal actin proteins and the SNARE complex. However, the precise mechanisms by which SCGN interacts with the SNARE complex and facilitates synaptic exocytosis are still unclear. Recently, Qin et al. [8] published a report in PNAS revealing that SCGN interacts directly with SNAP-25 in complex with Ca2? but not with the assembled SNARE complex. Crystal structure experiments further indicated that the SNAP-25 peptide specifically binds to a relatively small fragment within domain III of SCGN through hydrophobic interactions and multiple hydrogen bonds. Moreover, SCGN facilitates the accumulation of SNAP-25 at the plasma membrane (PM) by functioning as an intimate chaperone and inhibits the assembly of the SNARE complex b
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