Flexible pivoting of dynamin pleckstrin homology domain catalyzes fission: insights into molecular degrees of freedom

Baratam, K and Jha, K and Srivastava, A (2021) Flexible pivoting of dynamin pleckstrin homology domain catalyzes fission: insights into molecular degrees of freedom. In: Molecular Biology of the Cell, 32 (14). pp. 1306-1319.

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Abstract

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 1) the binding of PHD to PIP2-containing membranes modulates the lipids toward fission-favoring conformations and softens the membrane, and 2) 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 that 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. © 2021 Baratam, Jha, and Srivastava. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution�Noncommercial�Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Item Type:	Journal Article
Publication:	Molecular Biology of the Cell
Publisher:	American Society for Cell Biology
Additional Information:	The copyright for this article belongs to Authors
Department/Centre:	Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited:	09 Dec 2021 09:30
Last Modified:	09 Dec 2021 09:30
URI:	http://eprints.iisc.ac.in/id/eprint/69608

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