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    • In neurons and neuroendocrine cells

    2022-07-12

    In neurons and neuroendocrine cells, the productive fusion pathway is thought to initiate with the Munc18-1/Syx1 complex (Ma et al., 2013, Hughson, 2013, Lai et al., 2017). The Munc13-1 MUN domain is able to catalyze opening of Syx1 (the transition from the Munc18-1/Syx1 complex to the SNARE complex in the presence of SN25 and Syb2) (Ma et al., 2011, Wang et al., 2017). Despite remarkable structural similarity to the MUN domain, CAPS-1 failed to catalyze opening of Syx1, likely because the DAMH domain lacks the NF pocket that is characteristic of the MUN domain (Figure 2). Instead, CAPS-1 inhibits the ability of Munc13-1 to catalyze opening of Syx1 in a dose-dependent manner, suggesting a molecular link between the roles of CAPS-1 and Munc13-1 in SNARE complex formation. The identified interaction between the DAMH and MUN domains might account for the inhibitory effect of CAPS-1, according to the observation that the DAMH domain displaced the MUN domain from the Munc18-1/Syx1 complex in a dose-dependent manner (Figures 3 and S5). On the other hand, CAPS-1 and Munc13-1 are PIP2 Epiandrosterone mg proteins and contain critical domains that are responsible for binding to PIP2 clusters in the plasma membrane. CAPS-1 binds to PIP2 via its PH domain, whereas Munc13-1 binds to PIP2 in a Ca2+-dependent manner via its C2B domain (Shin et al., 2010, James et al., 2010). The Ca2+-independent PH-PIP2 interaction would be expected to dominate the Ca2+-dependent C2B-PIP2 interaction under resting conditions, impeding entry of Munc13-1 into PIP2-rich fusion sites. Taken together, these results suggest that CAPS-1 gates the initiation of SNARE complex formation during the early stage of exocytosis, in which both the PH-PIP2 and DAMH-MUN interactions collectively reduce the access of Munc13-1 to the Munc18-1/Syx1 complex, rendering the docked DCVs and SVs unable to proceed toward the priming stage that requires opening of Syx1. In neuroendocrine cells, intracellular Ca2+ plays an important role in accelerating the vesicle docking reaction via Ca2+-dependent vesicle recruitment and maturation (Voets, 2000, Becherer and Rettig, 2006). Particularly, both CAPS and Munc13 can facilitate vesicle recruitment to PIP2-rich membranes in a Ca2+-dependent manner (Kabachinski et al., 2016, Kreutzberger et al., 2017, Junge et al., 2004, Zikich et al., 2008). The Ca2+-dependent C2B-PIP2 interaction enables Munc13 to be enriched at the PIP2-rich fusion sites (Shin et al., 2010, Kabachinski et al., 2014), where some Munc13 molecules that escape CAPS binding and inhibition would be accessible to the Munc18-1/Syx1 complex and, thus, be available to catalyze opening of Syx1. In this scenario, when Syx1 is open and SN25 arrives, binding of CAPS to the Syx1/SN25 complex further stabilizes the open state of Syx1, which prevents Syx1 from folding back to its closed state bound to Munc18-1 and promotes Syb2 binding for SNARE complex formation. This model is consistent with previous results indicating that CAPS-1 binds preferentially to the open conformation of Syx1 (Daily et al., 2010, Parsaud et al., 2013) and suggests strong cooperation between CAPS and Munc13 in SNARE complex formation. In neurons, complexin-1 and Syt1 may additionally work together with CAPS and Munc13 to orchestrate SNARE complex formation, which eventually enables fusion to occur rapidly and efficiently in response to Ca2+ influx (Kreutzberger et al., 2017, Lai et al., 2017). Hence, our results suggest that the sequential and cooperative actions of CAPS and Munc13 in SNARE complex formation may underlie the nonredundancy of Munc13 and CAPS in exocytosis. It is noteworthy that, under conditions of increased DAG levels (e.g., Ca2+-dependent activation of phospholipase C induced by strong stimulus strength [or high-frequency stimulation] that leads to PIP2 metabolism to DAG; Kabachinski et al., 2014, Jockusch et al., 2007), Munc13 and CAPS would be expected to rearrange their positions and orientations with respect to the plasma membrane, which alters the protein requirement for exocytosis from a CAPS-Munc13-dependent mode to a Munc13-dependent mode (Kabachinski et al., 2014). The Munc13-dependent mode correlates with the stringent requirement of Munc13 in multiple Ca2+-dependent forms of synaptic plasticity (Rhee et al., 2002, Shin et al., 2010, de Jong and Fioravante, 2014).