How Does Liquid-Liquid Phase Separation in Model Membranes Reflect Cell Membrane Heterogeneity?

Sych, Taras; Gurdap, Cenk Onur; Wedemann, Linda; Sezgin, Erdinç

doi:10.3390/membranes11050323

Cited by 37 publications

(53 citation statements)

References 122 publications

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“… 31 , 33 In general, the two coexisting phases in different model systems and in vivo have different levels of mutual similarity. 34 − 37 These findings indeed suggest that the putative rafts likely differ from the L o phase observed in synthetic vesicles more than only by their size, 21 , 28 and some of these factors might also be temperature-dependent. 38 …”

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confidence: 65%

“…Importantly, it is unclear whether the L o phase observed in phase-separated vesicles differs structurally from that observed for the same mixture at physiological T and whether the former is a faithful model for plasma cell membrane heterogeneity. 28 Surprisingly, raft-associated proteins partition to the L d phase in phase-separated synthetic vesicles, 29 although the same proteins can locate to the ordered phase in phase-separated GMPVs. 30 Moreover, there are even differences between the partitioning behavior of proteins in GMPVs 31 and plasma membrane spheres 32 since the latter can maintain phase separation at higher temperatures due to mechanisms not present in model systems.…”

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confidence: 99%

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The Two Faces of the Liquid Ordered Phase

Schachter

Paananen

Fábián

et al. 2022

J. Phys. Chem. Lett.

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Coexisting liquid ordered (L o ) and liquid disordered (L d ) lipid phases in synthetic and plasma membrane-derived vesicles are commonly used to model the heterogeneity of biological membranes, including their putative ordered rafts. However, raft-associated proteins exclusively partition to the L d and not the L o phase in these model systems. We believe that the difference stems from the different microscopic structures of the lipid rafts at physiological temperature and the L o phase studied at room temperature. To probe this structural diversity across temperatures, we performed atomistic molecular dynamics simulations, differential scanning calorimetry, and fluorescence spectroscopy on L o phase membranes. Our results suggest that raft-associated proteins are excluded from the L o phase at room temperature due to the presence of a stiff, hexagonally packed lipid structure. This structure melts upon heating, which could lead to the preferential solvation of proteins by order-preferring lipids. This structural transition is manifested as a subtle crossover in membrane properties; yet, both temperature regimes still fulfill the definition of the L o phase. We postulate that in the compositionally complex plasma membrane and in vesicles derived therefrom, both molecular structures can be present depending on the local lipid composition. These structural differences must be taken into account when using synthetic or plasma membrane-derived vesicles as a model for cellular membrane heterogeneity below the physiological temperature.

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confidence: 65%

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confidence: 99%

The Two Faces of the Liquid Ordered Phase

Schachter

Paananen

Fábián

et al. 2022

J. Phys. Chem. Lett.

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“…In addition to membrane phospholipids, non-phospholipid membrane lipid molecules are also distributed nonrandomly. For example, cholesterol can affect membrane lipid distributions, and cholesterol is often found enriched in specific membrane domains [53][54][55]. Cholesterol distribution is thought to be due, in part, to its affinity for both the fluid and solid phases of membrane lipids [42][43][44][45].…”

Section: Membrane Component Interactions In Cell Membranesmentioning

confidence: 99%

“…Cholesterol distribution is thought to be due, in part, to its affinity for both the fluid and solid phases of membrane lipids [42][43][44][45]. Cholesterol partitions into liquid-ordered and disordered phases to roughly the same extent, but this partitioning can differently modify the properties of these dissimilar membrane lipid phases [54,55]. Lipids can also modify certain physical properties of membranes [56].…”

Section: Membrane Component Interactions In Cell Membranesmentioning

confidence: 99%

A Brief Introduction to Some Aspects of the Fluid–Mosaic Model of Cell Membrane Structure and Its Importance in Membrane Lipid Replacement

Nicolson

Ferreira

2021

Membranes

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Early cell membrane models placed most proteins external to lipid bilayers in trimolecular structures or as modular lipoprotein units. These thermodynamically untenable structures did not allow lipid lateral movements independent of membrane proteins. The Fluid–Mosaic Membrane Model accounted for these and other properties, such as membrane asymmetry, variable lateral mobilities of membrane components and their associations with dynamic complexes. Integral membrane proteins can transform into globular structures that are intercalated to various degrees into a heterogeneous lipid bilayer matrix. This simplified version of cell membrane structure was never proposed as the ultimate biomembrane description, but it provided a basic nanometer scale framework for membrane organization. Subsequently, the structures associated with membranes were considered, including peripheral membrane proteins, and cytoskeletal and extracellular matrix components that restricted lateral mobility. In addition, lipid–lipid and lipid–protein membrane domains, essential for cellular signaling, were proposed and eventually discovered. The presence of specialized membrane domains significantly reduced the extent of the fluid lipid matrix, so membranes have become more mosaic with some fluid areas over time. However, the fluid regions of membranes are very important in lipid transport and exchange. Various lipid globules, droplets, vesicles and other membranes can fuse to incorporate new lipids or expel damaged lipids from membranes, or they can be internalized in endosomes that eventually fuse with other internal vesicles and membranes. They can also be externalized in a reverse process and released as extracellular vesicles and exosomes. In this Special Issue, the use of membrane phospholipids to modify cellular membranes in order to modulate clinically relevant host properties is considered.

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“…Liquid-liquid phase separation (LLPS) is a subset of PM heterogeneity caused by lipidlipid and lipid-protein interactions. Model membranes are widely used as a synthetic proxy of such heterogeneity in the PM 5 . In these simple model membrane systems, saturated lipids form a liquid-ordered phase (Lo) with the help of cholesterol, and unsaturated lipids form a liquid-disordered phase (Ld).…”

Section: Introductionmentioning

confidence: 99%

Influence of the extracellular domain size on the dynamic behavior of membrane proteins

Wedemann

Gurdap

Sych

et al. 2021

Preprint

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The dynamic behavior of the plasma membrane proteins mediates various cellular processes, such as cell-cell interactions, transmembrane transport and signaling. It is widely accepted that the dynamics of the membrane proteins is determined either by the interactions of the transmembrane domain with the surrounding lipids or by the interaction of the intracellular domain with cytosolic components such as cortical actin. However, the impact of the extracellular domains (ECDs) on the dynamics of membrane proteins is rather unexplored. Here, we investigate how the ECD size influences protein dynamics in lipid bilayer. We reconstitute ECDs of different molecular weights and heights in model membrane systems and analyze ECD-driven protein sorting in lipid domains as well as protein mobility. We observe that increasing the ECD size leads to a decrease in ordered domain partitioning as well as diffusivity. Our data suggests a critical role of the ECDs on membrane protein behavior in the plasma membrane and paves the way to a more complete understanding of membrane protein dynamics that includes interaction with the extracellular matrix and glycocalyx in health and disease.

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How Does Liquid-Liquid Phase Separation in Model Membranes Reflect Cell Membrane Heterogeneity?

Cited by 37 publications

References 122 publications

The Two Faces of the Liquid Ordered Phase

The Two Faces of the Liquid Ordered Phase

A Brief Introduction to Some Aspects of the Fluid–Mosaic Model of Cell Membrane Structure and Its Importance in Membrane Lipid Replacement

Influence of the extracellular domain size on the dynamic behavior of membrane proteins

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