The tilted helix model of dynamin oligomers

Abstract

Dynamin proteins assemble into characteristic helical structures around necks of clathrin-coated membrane buds. Hydrolysis of dynamin-bound GTP results in both fission of the membrane neck and partial disruption of the dynamin oligomer. Imaging by atomic force microscopy reveals that, on GTP hydrolysis, dynamin oligomers undergo a dynamic remodeling and lose their distinctive helical shape. While breakup of the dynamin helix is a critical stage in clathrin-mediated endocytosis, the mechanism for this remodeling of the oligomer has not been resolved. In this paper, we formulate an analytical, elasticity-based model for the reshaping and disassembly of the dynamin scaffold. We predict that the shape of the oligomer is modulated by the orientation of dynamin’s pleckstrin homology (PH) domain relative to the underlying membrane. Our results indicate that tilt of the PH domain drives deformation and fragmentation of the oligomer, in agreement with experimental observations. This model motivated the introduction of the tilted helix: a curve that maintains a fixed angle between its normal and the normal of the embedding surface. Our findings highlight the importance of tilt as a key regulator of size and morphology of membrane-bound oligomers.

Flexible pivoting of dynamin PH-domain catalyzes fission: Insights into molecular degrees of freedom

“…Previous results from 3D reconstructions of dynamin mutants trapped in a constricted state (27,28,82) as well as data from biochemical and multiple fluorescence spectroscopic approaches (18) suggest that the PHD can associate with the membrane in different orientations. Theoretical analyses of determinants that could lower the energy barrier for fission have invoked tilting of the PHD to conform with the evolving membrane curvature and thereby create a low-energy pathway for fission (23,29,88). Our multiscale simulations data validate these possibilities and provide molecular insights in terms of effects of PHD on membrane properties and lipid conformations and as well on the binding geometries and orientation stability of PHD on membrane, all of which may affect processes downstream of membrane binding.…”

Quantification and demonstration of the collective constriction-by-ratchet mechanism in the dynamin molecular motor

“…It is also assumed that nucleotide-driven conformational changes are limited to the MM. It should be noted that the proposed PH-domain–coupled tilt deformations of the dynamin filament ( 47 ) or filament clustering induced by the transition state analog vanadate ( 40 ) could induce deformations in the stalk tetramer that are inconsistent with its soft normal modes ( 16 ). These deformations could lead to breakages along the filament, which would provide additional filament ends where torque production and membrane scission could occur.…”

Quantification and demonstration of the constriction-by-rachet mechanism in the dynamin molecular motor

“…While modeling, additional simplifications were made. The dynamin filament was treated as an elastic ribbon whose local orientation with respect to the membrane remained fixed, even though it had been noticed that tilt deformations changing the orientation might additionally contribute to the breakup [42]. Moreover, axial symmetry of the membrane was assumed.…”