6L03

structure of PTP-MEG2 and MUNC18-1-pY145 peptide complex

Summary for 6L03

• Entry DOI: 10.2210/pdb6l03/pdb
• Descriptor: Tyrosine-protein phosphatase non-receptor type 9, stxbp1-pY145 peptide (3 entities in total)
• Functional Keywords: ptp-meg2, nsf, vesicle fusion, hydrolase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 36315.93

Authors

Xu, Y.F.,Chen, X.,Yu, X.,Sun, J.P. (deposition date: 2019-09-25, release date: 2020-09-30, Last modification date: 2024-10-23)

Primary citation

Xu, Y.F.,Chen, X.,Yang, Z.,Xiao, P.,Liu, C.H.,Li, K.S.,Yang, X.Z.,Wang, Y.J.,Zhu, Z.L.,Xu, Z.G.,Zhang, S.,Wang, C.,Song, Y.C.,Zhao, W.D.,Wang, C.H.,Ji, Z.L.,Zhang, Z.Y.,Cui, M.,Sun, J.P.,Yu, X.
PTP-MEG2 regulates quantal size and fusion pore opening through two distinct structural bases and substrates.
Embo Rep., 22:e52141-e52141, 2021

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 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 and MUNC18-1-pY sites. Further structural and biochemical analyses confirmed the interaction of PTP-MEG2 with MUNC18-1-pY or DYNAMIN2-pY through a distinct structural basis compared with that of the NSF-pY site. Our studies thus provide mechanistic insights in complex exocytosis processes.

PubMed: 33764618
DOI: 10.15252/embr.202052141

Experimental method

X-RAY DIFFRACTION (2.084 Å)