The neuronal dynamin1 functions in the release of synaptic vesicles by orchestrating the process of GTPase dependent membrane fission. Dynamin1 associates with the plasma membrane-localized phosphatidylinositol-4,5-bisphosphate (PIP2) through the centrally-located pleckstrin homology domain (PHD). The PHD is dispensable as fission (in model membranes) can be managed, even when the PHD-PIP2 interaction is replaced by a generic polyhistidine- or polylysine-lipid interaction. However, the absence of the PHD renders a dramatic dampening of the rate of fission. These observations suggest that the PHD-PIP2 containing membrane interaction could have evolved to expedite fission to fulfill the requirement of rapid kinetics of synaptic vesicle recycling. Here, we use a suite of multiscale modeling approaches to explore PHD-membrane interactions. Our results reveal that (a) the binding of PHD to PIP2-containing membranes modulates the lipids towards fission-favoring conformations and softens the membrane, and (b) PHD associates with membrane in multiple orientations using variable loops as pivots. We identify a new loop (VL4), which acts as an auxiliary pivot and modulates the orientation flexibility of PHD on the membrane — a mechanism we believe may be important for high fidelity dynamin collar assembly. Together, these insights provide a molecular-level understanding of the catalytic role of PHD in dynamin-mediated membrane fission. [Media: see text] [Media: see text] [Media: see text] [Media: see text]
The neuronal dynamin1 functions in the release of synaptic vesicles by orchestrating a process of GTPase-dependent membrane fission. Dynamin1 associates with the plasma membrane-localized phosphatidylinositol-4,5bisphosphate (PIP2) through the centrallylocated pleckstrin homology domain (PHD). The PHD is dispensable as fission can be managed even when the PHD-PIP2 interaction is replaced by a generic polyhistidine-or polylysine-lipid interaction. Remarkably however, the absence of the PHD renders a dramatic dampening of the rate of fission. These observations suggest that the PHD-PIP2 interaction could have evolved to expedite fission to fulfill the requirement of rapid kinetics of synaptic vesicle recycling. Here, we use a suite of multiscale modeling approaches that combine atomistic molecular dynamics simulations, mixed-resolution membrane mimetic models, coarse-grained molecular simulations and advanced free-energy sampling (metadynamics) methods to explore PHDmembrane interactions. Our results reveal that; (a) the binding of PHD to PIP2-containing membranes modulates the lipids towards fission-favoring conformations and overall softens the membrane thus rendering it pliable
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