{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Xu YF"],"funding":["National Science Fund for Distinguished Young Scholars","National Key Basic Research Program of China Grant","Key Research Project of the Natural Science Foundation of Beijing","National Natural Science Foundation of China","China Postdoctoral Science Foundation","National Institutes of Health","National Natural Science Foundation of China (NSFC)","Fundamental Research Funds of Shandong University","Shandong University Multidisciplinary Research and Innovation Team of Young Scholars","National Science Fund for Excellent Young Scholars","Academic promotion programme of Shandong First Medical University","HHS|National Institutes of Health (NIH)","Shandong Provincial Natural Science Foundation","COVID-19 Emergency Tackling Research Program of Shandong University","Natural Science Foundation of Shandong Province (Natural Science Foundation of Shandong)","Fundamental Research Fund of Shandong University","Natural Science Foundation of Shandong Province","SDU|Fundamental Research Fund of Shandong University","NCI NIH HHS","NSFC|National Science Fund for Distinguished Young Scholars (National Science Foundation for Distinguished Young Scholars)"],"pagination":["e52141"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8097337"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["22(5)"],"pubmed_abstract":["Tyrosine phosphorylation of secretion machinery proteins is a crucial regulatory mechanism for exocytosis. However, the participation of protein tyrosine phosphatases (PTPs) in different exocytosis stages has not been defined. Here we demonstrate that PTP-MEG2 controls multiple steps of catecholamine secretion. Biochemical and crystallographic analyses reveal key residues that govern the interaction between PTP-MEG2 and its substrate, a peptide containing the phosphorylated NSF-pY<sup>83</sup> site, specify PTP-MEG2 substrate selectivity, and modulate the fusion of catecholamine-containing vesicles. Unexpectedly, delineation of PTP-MEG2 mutants along with the NSF binding interface reveals that PTP-MEG2 controls the fusion pore opening through NSF independent mechanisms. Utilizing bioinformatics search and biochemical and electrochemical screening approaches, we uncover that PTP-MEG2 regulates the opening and extension of the fusion pore by dephosphorylating the DYNAMIN2-pY<sup>125</sup> and MUNC18-1-pY<sup>145</sup> sites. Further structural and biochemical analyses confirmed the interaction of PTP-MEG2 with MUNC18-1-pY<sup>145</sup> or DYNAMIN2-pY<sup>125</sup> through a distinct structural basis compared with that of the NSF-pY<sup>83</sup> site. Our studies thus provide mechanistic insights in complex exocytosis processes."],"journal":["EMBO reports"],"pubmed_title":["PTP-MEG2 regulates quantal size and fusion pore opening through two distinct structural bases and substrates."],"pmcid":["PMC8097337"],"funding_grant_id":["2017JQ02","2020QNQT002","81822008","82072676","ZR2017BC045","ZR2020ZD39","R01 CA069202","81773704","2018YFC1003600","2020M682190","CA69202","81825022","31701230","2020XGB02","81700473","2019QL009","Z200019"],"pubmed_authors":["Liu CH","Cui M","Zhao WD","Wang CH","Wang C","Zhang ZY","Zhu ZL","Zhang S","Yang XZ","Wang YJ","Xiao P","Ji ZL","Yang Z","Li KS","Song YC","Chen X","Xu YF","Xu ZG","Yu X","Sun JP"],"additional_accession":[]},"is_claimable":false,"name":"PTP-MEG2 regulates quantal size and fusion pore opening through two distinct structural bases and substrates.","description":"Tyrosine phosphorylation of secretion machinery proteins is a crucial regulatory mechanism for exocytosis. However, the participation of protein tyrosine phosphatases (PTPs) in different exocytosis stages has not been defined. Here we demonstrate that PTP-MEG2 controls multiple steps of catecholamine secretion. Biochemical and crystallographic analyses reveal key residues that govern the interaction between PTP-MEG2 and its substrate, a peptide containing the phosphorylated NSF-pY<sup>83</sup> site, specify PTP-MEG2 substrate selectivity, and modulate the fusion of catecholamine-containing vesicles. Unexpectedly, delineation of PTP-MEG2 mutants along with the NSF binding interface reveals that PTP-MEG2 controls the fusion pore opening through NSF independent mechanisms. Utilizing bioinformatics search and biochemical and electrochemical screening approaches, we uncover that PTP-MEG2 regulates the opening and extension of the fusion pore by dephosphorylating the DYNAMIN2-pY<sup>125</sup> and MUNC18-1-pY<sup>145</sup> sites. Further structural and biochemical analyses confirmed the interaction of PTP-MEG2 with MUNC18-1-pY<sup>145</sup> or DYNAMIN2-pY<sup>125</sup> through a distinct structural basis compared with that of the NSF-pY<sup>83</sup> site. Our studies thus provide mechanistic insights in complex exocytosis processes.","dates":{"release":"2021-01-01T00:00:00Z","publication":"2021 May","modification":"2026-05-31T09:47:51.424Z","creation":"2025-02-18T23:32:21.618Z"},"accession":"S-EPMC8097337","cross_references":{"pubmed":["33764618"],"doi":["10.15252/embr.202052141"]}}