Intrinsically Disordered Proteins Drive Membrane Curvature

Busch, David J.; Houser, Justin R.; Hayden, Carl C.; Sherman, Michael B; Lafer, Eileen M.; Stachowiak, Jeanne C.

doi:10.1016/j.bpj.2015.11.270

Cited by 31 publications

(52 citation statements)

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“…For example, work from the Silvius laboratory suggests that despite their lack of an internalization motif, small glycosylphosphatidylinositol-anchored proteins can be internalized by CCSs, whereas larger glycosylphosphatidylinositol-anchored proteins are excluded (12). In line with these findings, Mettlen and Schmid have shown that overexpression of the bulky low-density lipoprotein receptor presents an obstacle to internalization (13), which is similar to findings for cargo molecules with bulky, intrinsically disordered extracellular domains (14). Additionally, in studies of Sec13p mutants and Sec13p-independent cargos of the COPII pathway, Copic and Miller suggested that bulky or asymmetrically shaped cargo proteins are more difficult for the COPII coat to accommodate in comparison to smaller cargo proteins (15).…”

Section: Introductionmentioning

confidence: 68%

Entropic Control of Receptor Recycling Using Engineered Ligands

DeGroot

Busch

Hayden

et al. 2018

Biophysical Journal

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Receptor internalization by endocytosis regulates diverse cellular processes, from the rate of nutrient uptake to the timescale of essential signaling events. The established view is that internalization is tightly controlled by specific protein-binding interactions. However, recent work suggests that physical aspects of receptors influence the process in ways that cannot be explained by biochemistry alone. Specifically, work from several groups suggests that increasing the steric bulk of receptors may inhibit their uptake by multiple types of trafficking vesicles. How do biochemical and biophysical factors work together to control internalization? Here, we show that receptor uptake is well described by a thermodynamic trade-off between receptor-vesicle binding energy and the entropic cost of confining receptors within endocytic vesicles. Specifically, using large ligands to acutely increase the size of engineered variants of the transferrin receptor, we demonstrate that an increase in the steric bulk of a receptor dramatically decreases its probability of uptake by clathrin-coated structures. Further, in agreement with a simple thermodynamic analysis, all data collapse onto a single trend relating fractional occupancy of the endocytic structure to fractional occupancy of the surrounding plasma membrane, independent of receptor size. This fundamental scaling law provides a simple tool for predicting the impact of receptor expression level, steric bulk, and the size of endocytic structures on receptor uptake. More broadly, this work suggests that bulky ligands could be used to drive the accumulation of specific receptors at the plasma membrane surface, providing a biophysical tool for targeted modulation of signaling and metabolism from outside the cell.

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Section: Introductionmentioning

confidence: 68%

Entropic Control of Receptor Recycling Using Engineered Ligands

DeGroot

Busch

Hayden

et al. 2018

Biophysical Journal

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“…Such entropy-driven mechanism has been demonstrated computationally showing that grafted polymers may induce curvature (Bickel et al 2001, Breidenich et al 2000 and later in experiments where tethered DNA or proteins on the membrane generated tubules (Nikolov et al 2007, Stachowiak et al 2012. Proteins with the BAR domain contain a number of other regions, which contain disordered sub-regions that could contribute to crowding-generated membrane curvature (Busch et al 2015). BAR protein-induced membrane deformation can occur in more subtle ways, but with potentially significant biological consequences.…”

Section: Mechanisms Of Curvature Generation By Bar Proteinsmentioning

confidence: 96%

Curving Cells Inside and Out: Roles of BAR Domain Proteins in Membrane Shaping and Its Cellular Implications

Šimunović

Evergren

Callan-Jones

et al. 2019

Annu. Rev. Cell Dev. Biol.

121

102

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Many cellular processes rely on precise and timely deformation of the cell membrane. While many proteins participate in membrane reshaping and scission, usually in highly specialized ways, Bin/amphiphysin/Rvs (BAR) domain proteins play a pervasive role, as they not only participate in many aspects of cell trafficking but also are highly versatile membrane remodelers. Subtle changes in the shape and size of the BAR domain can greatly impact the way in which BAR domain proteins interact with the membrane. Furthermore, the activity of BAR domain proteins can be tuned by external physical parameters, and so they behave differently depending on protein surface density, membrane tension, or membrane shape. These proteins can form 3D structures that mold the membrane and alter its liquid properties, even promoting scission under various circumstances.As such, BAR domain proteins have numerous roles within the cell. Endocytosis is among the most highly studied processes in which BAR domain proteins take on important roles. Over the years, a more complete picture has emerged in which BAR domain proteins are tied to almost all intracellular compartments; examples include endosomal sorting and tubular networks in the endoplasmic reticulum and T-tubules. These proteins also have a role in autophagy, and their activity has been linked with cancer. Here, we briefly review the history of BAR domain protein discovery, discuss the mechanisms by which BAR domain proteins induce curvature, and attempt to settle important controversies in the field. Finally, we review BAR domain proteins in the context of a cell, highlighting their emerging roles in cell signaling and organelle shaping.

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“…When proteins adsorb on the membrane surface at sufficiently high density, steric repulsion between them generates lateral pressure which leads to membrane deformation . Intrinsically disordered proteins, which have been recognized as potent membrane curvature generators, presumably operate through the crowding mechanism . Integral membrane proteins and lipid composition can also generate membrane curvature .…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of negative membrane curvature sensing and generation by ESCRT III subunit Snf7

2020

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Certain proteins have the propensity to bind to negatively curved membranes and generate negative membrane curvature. The mechanism of action of these proteins is much less studied and understood than those that sense and generate positive curvature. In this work, we use implicit membrane modeling to explore the mechanism of an important negative curvature sensing and generating protein: the main ESCRT III subunit Snf7. We find that Snf7 monomers alone can sense negative curvature and that curvature sensitivity increases for dimers and trimers. We have observed spontaneous bending of Snf7 oligomers into circular structures with preferred radius of~20 nm. The preferred curvature of Snf7 filaments is further confirmed by the simulations of preformed spirals on a cylindrical membrane surface. Snf7 filaments cannot bind with the same interface to flat and curved membranes. We find that even when a filament has the preferred radius, it is always less stable on the flat membrane surface than on the interior cylindrical membrane surface. This provides an additional energy for membrane bending which has not been considered in the spiral spring model. Furthermore, the rings on the cylindrical spirals are bridged together by helix 4 and hence are extra stabilized compared to the spirals on the flat membrane surface. K E Y W O R D Scomputer simulation, ESCRT III, lipid bilayer, membrane curvature sensing and generation, Snf7

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Intrinsically Disordered Proteins Drive Membrane Curvature

Cited by 31 publications

References 0 publications

Entropic Control of Receptor Recycling Using Engineered Ligands

Entropic Control of Receptor Recycling Using Engineered Ligands

Curving Cells Inside and Out: Roles of BAR Domain Proteins in Membrane Shaping and Its Cellular Implications

Mechanisms of negative membrane curvature sensing and generation by ESCRT III subunit Snf7

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