Membrane remodeling and mechanics: Experiments and simulations of α-Synuclein

West, Allison; Brummel, Benjamin E.; Braun, Anthony R.; Rhoades, Elizabeth; Sachs, Jonathan N.

doi:10.1016/j.bbamem.2016.03.012

Cited by 45 publications

(58 citation statements)

References 193 publications

(271 reference statements)

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“…Collectively, the protein-induced changes in local curvature fields conspire to induce the formation of long tubule protrusions from flat membrane sheets and GUVs 1,8 . Exactly what controls this process and how it develops remain open and evolving questions in the field 10,11 .…”

Section: Introductionmentioning

confidence: 99%

α-Synuclein’s Uniquely Long Amphipathic Helix Enhances its Membrane Binding and Remodeling Capacity

et al. 2017

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α-Synuclein is the primary protein found in Lewy bodies, the protein and lipid aggregates associated with Parkinson’s disease and Lewy body dementia. The protein folds into a uniquely long amphipathic α-helix (AH) when bound to a membrane, and at high enough concentrations induces large scale remodeling of membranes (tubulation and vesiculation). By engineering a less hydrophobic variant of α-Synuclein, we previously showed that the energy associated with binding of α-Synuclein’s AH correlates with the extent of membrane remodeling1. Here, we combine fluorescence correlation spectroscopy, electron microscopy and vesicle clearance assays with coarsegrained molecular dynamics simulations to test the impact of decreasing the length of the amphipathic helix on membrane binding energy and tubulation. We show that truncation of α-Synuclein’s AH length by approximately 15% reduces both its membrane binding affinity (by five-fold) and membrane remodeling capacity (by nearly 50% on a per mole of bound protein basis). Results from simulations correlate well with the experiments and lend support to the idea that at high protein density there is a stabilization of individual, protein-induced membrane curvature fields. The extent to which these curvature fields are stabilized, a function of binding energy, dictates the extent of tubulation. Somewhat surprisingly, we find that this stabilization does not correlate directly with the geometric distribution of the proteins on the membrane surface.

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Section: Introductionmentioning

confidence: 99%

α-Synuclein’s Uniquely Long Amphipathic Helix Enhances its Membrane Binding and Remodeling Capacity

et al. 2017

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“…On the other hand, there is minimal change in ellipticity around the T m in the upscan, with only one broad peak around 40ºC (accompanied by a shoulder around 30ºC), indicating the unfolding of the protein in the absence of structural changes in the lipid membrane. Finally, we studied the morphology and size of the lipid assemblies after a temperature scan, performed both in the presence and absence of αSyn, to check for possible remodeling effects of αSyn on the SUVs (33,46). Supernatants were freshly collected and analyzed after the ultracentrifuge spin performed at the end of the temperature cycling, done to remove larger lipid aggregates formed by the fusion of PC SUVs below their T m (47).…”

Section: Resultsmentioning

confidence: 99%

Reconstitution of Helical Soluble α-Synuclein through Transient Interaction with Lipid Interfaces

Rovere

Fonseca‐Ornelas

et al. 2017

Preprint

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α-synuclein (αSyn) is one of the key players in the pathogenesis of Parkinson's disease (PD) and other synucleinopathies. Its misfolding and subsequent aggregation into intracellular inclusions are the pathological hallmark of these diseases and may also play a central role in the molecular cascade leading to neurodegeneration. In this work, we report the existence of a novel soluble α-helical conformer of αSyn, an archetypal "intrinsically disordered protein" (IDP), obtained through transient interaction with lipid interfaces. We describe how the stability of this conformer is highly dependent on the continuous, dynamic oligomerization of the folded species. The conformational space of αSyn appears to be highly context-dependent, and lipid bilayers might play crucial roles as molecular chaperones for cytosolic species in a cellular environment, as they do in the case of this previously unreported structure. Significance StatementBoth genetic and histopathologic evidence tie α-synuclein (αSyn) to the pathogenesis of Parkinson's disease (PD), a widespread neurodegenerative disorder. Lipids play a central role in the dynamics of αSyn in physiology and disease. αSyn undergoes a coil-to-helix transition when binding to lipid vesicles and it is involved in the regulation of synaptic vesicle trafficking. Furthermore, recently discovered αhelical, aggregation-resistant "multimers" of αSyn could constitute a protective conformational pathway. We report the existence of a folded, lipid-unbound αSyn conformer that forms upon transient interaction with lipids and is stabilized by dynamic homooligomerization, suggesting that synaptic activity could modulate resistance towards aggregation. Our results are therefore important both for the molecular pathology of PD and the structural biology of intrinsically disordered proteins.

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“…(D) Coarse-grained molecular dynamics simulation of 48 α -synuclein molecules forming a tubule on a bilayer containing 85 000 lipids. Reprinted from [76], Copyright 2016, with permission from Elsevier. (E) A coarse-grained molecular dynamics simulation of 8 ENTH domains anchored to a lipid bilayer.…”

Section: Figurementioning

confidence: 99%

“…Several studies have used this method to qualitatively describe how bound proteins alter the average height/deflection of a free bilayer [76, 77, 83–85]. Using bilayer deflection as a proxy for curvature introduces the first of several challenges for understanding protein-mediated membrane sculpting: are proteins sensing or creating curvature?…”

Section: Introductionmentioning

confidence: 99%

Biophysics of membrane curvature remodeling at molecular and mesoscopic lengthscales

Ramakrishnan

Bradley

Tourdot

et al. 2018

J. Phys.: Condens. Matter

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At the micron scale, where cell organelles display an amazing complexity in their shape and organization, the physical properties of a biological membrane can be better-understood using continuum models subject to thermal (stochastic) undulations. Yet, the chief orchestrators of these complex and intriguing shapes are a specialized class of membrane associating often peripheral proteins called curvature remodeling proteins (CRPs) that operate at the molecular level through specific protein-lipid interactions. We review multiscale methodologies to model these systems at the molecular as well as at the mesoscopic and cellular scales, and also present a free energy perspective of membrane remodeling through the organization and assembly of CRPs. We discuss the morphological space of nearly planar to highly curved membranes, methods to include thermal fluctuations, and review studies that model such proteins as curvature fields to describe the emergent curved morphologies. We also discuss several mesoscale models applied to a variety of cellular processes, where the phenomenological parameters (such as curvature field strength) are often mapped to models of real systems based on molecular simulations. Much insight can be gained from the calculation of free energies of membranes states with protein fields, which enable accurate mapping of the state and parameter values at which the membrane undergoes morphological transformations such as vesiculation or tubulation. By tuning the strength, anisotropy, and spatial organization of the curvature-field, one can generate a rich array of membrane morphologies that are highly relevant to shapes of several cellular organelles. We review applications of these models to budding of vesicles commonly seen in cellular signaling and trafficking processes such as clathrin mediated endocytosis, sorting by the ESCRT protein complexes, and cellular exocytosis regulated by the exocyst complex. We discuss future prospects where such models can be combined with other models for cytoskeletal assembly, and discuss their role in understanding the effects of cell membrane tension and the mechanics of the extracellular microenvironment on cellular processes.

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Membrane remodeling and mechanics: Experiments and simulations of α-Synuclein

Cited by 45 publications

References 193 publications

α-Synuclein’s Uniquely Long Amphipathic Helix Enhances its Membrane Binding and Remodeling Capacity

α-Synuclein’s Uniquely Long Amphipathic Helix Enhances its Membrane Binding and Remodeling Capacity

Reconstitution of Helical Soluble α-Synuclein through Transient Interaction with Lipid Interfaces

Biophysics of membrane curvature remodeling at molecular and mesoscopic lengthscales

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