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Review
. 2018 Aug 3;430(16):2293-2308.
doi: 10.1016/j.jmb.2018.03.024. Epub 2018 Apr 5.

Structure Versus Stochasticity-The Role of Molecular Crowding and Intrinsic Disorder in Membrane Fission

Wilton T Snead  1 , Jeanne C Stachowiak  2
Affiliations
Review

Structure Versus Stochasticity-The Role of Molecular Crowding and Intrinsic Disorder in Membrane Fission

Wilton T Snead et al. J Mol Biol. .

Abstract

Cellular membranes must undergo remodeling to facilitate critical functions including membrane trafficking, organelle biogenesis, and cell division. An essential step in membrane remodeling is membrane fission, in which an initially continuous membrane surface is divided into multiple, separate compartments. The established view has been that membrane fission requires proteins with conserved structural features such as helical scaffolds, hydrophobic insertions, and polymerized assemblies. In this review, we discuss these structure-based fission mechanisms and highlight recent findings from several groups that support an alternative, structure-independent mechanism of membrane fission. This mechanism relies on lateral collisions among crowded, membrane-bound proteins to generate sufficient steric pressure to drive membrane vesiculation. As a stochastic process, this mechanism contrasts with the paradigm that deterministic protein structures are required to drive fission, raising the prospect that many more proteins may participate in fission than previously thought. Paradoxically, our recent work suggests that intrinsically disordered domains may be among the most potent drivers of membrane fission, owing to their large hydrodynamic radii and substantial chain entropy. This stochastic view of fission also suggests new roles for the structure-based fission proteins. Specifically, we hypothesize that in addition to driving fission directly, the canonical fission machines may facilitate the enrichment and organization of bulky disordered protein domains in order to promote membrane fission by locally amplifying protein crowding.

Keywords: intrinsically disordered proteins; membrane biophysics; membrane fission; membrane traffic; protein crowding.

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Figures

Figure 1
Figure 1
Membrane fission throughout the cell. Each fission event requires significant energetic contributions from diverse protein machines. Conserved structural features and assembly properties are found in all of the fission proteins highlighted here, including hydrophobic insertions, scaffolding, and polymerization. Clathrin cage structure from Fotin et al, Nature 2004 [13]. Super-constricted dynamin helix: EMDB 2701 [14]. Endophilin N-BAR scaffold on a 28 nm-diameter membrane tube: EMDB 2007 [15]. COPII cage structure: EMDB 1232 [16].
Figure 2
Figure 2
Protein crowding provides a stochastic driving force for membrane bending and fission. (A) Collisions among membrane-bound proteins densely covering the membrane surface generate steric pressure. The membrane takes on curvature to relieve steric pressure until crowding energy is balanced by the bending energy of the membrane. (B) When wild-type ENTH domain is bound to giant unilamellar vesicles at sufficient coverage, the resulting steric pressure drove membrane tubulation. Image from Stachowiak et al, Nature Cell Biology 2012 [76]. (C) Wild-type ENTH drove membrane fission in addition to membrane curvature, as evidenced by the presence of highly curved membrane tubules (black arrows) and fission vesicles (red arrowheads) after exposure of initially low-curvature vesicles to protein. (D) A version of the ENTH domain lacking the membrane-inserting amphipathic helix (his-ENTH) and recruited to membranes by a histidine-NTA interaction formed highly curved fission vesicles when crowded at membrane surfaces. (E) Histidine-tagged green fluorescent protein (his-GFP) also drove potent membrane fission by protein crowding, despite lacking any structural feature traditionally associated with fission. Data in (C – E) from Snead et al, PNAS 2017 [12].
Figure 3
Figure 3
Intrinsically disordered proteins generate entropic pressure and are efficient drivers of membrane bending and fission. (A) Axonal neurofilaments are an important cellular example of entropic pressure generated by IDP domains. Neurofilament IDPs radiate outward along filaments, creating zones of exclusion which repel neighboring filaments and control filament spacing. Neurofilament IDP domains thereby determine the overall diameter of the axon. Electron micrograph from Hirokawa et al, Journal of Cell Biology 1984 [96]. (B) IDP domains crowd membrane surfaces more efficiently than well-folded proteins of equal molecular weight. IDP domains therefore require fewer protein copies to drive membrane bending and fission through a crowding mechanism, in comparison to well-folded domains of equal molecular weight.
Figure 4
Figure 4
Potential mechanisms of organizing and controlling protein crowding to drive membrane bending and fission.
See this image and copyright information in PMC

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