PTP-MEG2 regulates quantal size and fusion pore opening through two distinct structural bases and substrates.
EMBO Rep
; 22(5): e52141, 2021 05 05.
Article
in English
| MEDLINE | ID: covidwho-1151026
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-pY83 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-pY125 and MUNC18-1-pY145 sites. Further structural and biochemical analyses confirmed the interaction of PTP-MEG2 with MUNC18-1-pY145 or DYNAMIN2-pY125 through a distinct structural basis compared with that of the NSF-pY83 site. Our studies thus provide mechanistic insights in complex exocytosis processes.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Protein Tyrosine Phosphatases
/
Protein Tyrosine Phosphatases, Non-Receptor
Language:
English
Journal:
EMBO Rep
Journal subject:
Molecular Biology
Year:
2021
Document Type:
Article
Affiliation country:
Embr.202052141
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