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PTP‐MEG2 regulates quantal size and fusion pore opening through two distinct structural bases and substrates

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.