Membrane phase separation drives responsive assembly of receptor signaling domains

Shelby, Sarah A.; Castello-Serrano, Ivan; Wisser, Kathleen; Levental, Ilya; Veatch, Sarah L.

doi:10.1038/s41589-023-01268-8

Cited by 67 publications

(32 citation statements)

References 62 publications

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“…Of note, although lipids typical for the cytoplasmic leaflet do not show phase separation when studied in model bilayers, 26 the cortical actin cytoskeleton was observed to induce the formation of more ordered domains 64 in cells. Consistently, differential partitioning of protein anchors in phase‐separated model membranes correlated well with the differential localization of the same anchors in cell membranes, indicating the presence of tunable signaling domains in the plasma membrane 65 . Together, it appears plausible that each membrane protein possesses its characteristic nanoenvironment, 66 which modulates its mobility and conformational flexibility.…”

Section: Discussionmentioning

confidence: 63%

“…Consistently, differential partitioning of protein anchors in phase-separated model membranes correlated well with the differential localization of the same anchors in cell membranes, indicating the presence of tunable signaling domains in the plasma membrane. 65 Together, it appears plausible that each membrane protein possesses its characteristic nanoenvironment, 66 which modulates its mobility and conformational flexibility. In this context we would like to refer the reader to the rich literature on the presence of membrane domains in the plasma membrane (for reviews see [67][68][69][70] ) and discussions on the controversy in this field.…”

Section: Discussionmentioning

confidence: 99%

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The asymmetric plasma membrane—A composite material combining different functionalities?

Schütz,

Pabst

2023

BioEssays

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One persistent puzzle in the life sciences is the asymmetric lipid composition of the cellular plasma membrane: while the exoplasmic leaflet is enriched in lipids carrying predominantly saturated fatty acids, the cytoplasmic leaflet hosts preferentially lipids with (poly‐)unsaturated fatty acids. Given the high energy requirements necessary for cells to maintain this asymmetry, the question naturally arises regarding its inherent benefits. In this paper, we propose asymmetry to represent a potential solution for harmonizing two conflicting requirements for the plasma membrane: first, the need to build a barrier for the uncontrolled influx or efflux of substances; and second, the need to form a fluid and dynamic two‐dimensional substrate for signaling processes. We hence view here the plasma membrane as a composite material, where the exoplasmic leaflet is mainly responsible for the functional integrity of the barrier and the cytoplasmic leaflet for fluidity. We reinforce the validity of the proposed mechanism by presenting quantitative data from the literature, along with multiple examples that bolster our model.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

The asymmetric plasma membrane—A composite material combining different functionalities?

Schütz,

Pabst

2023

BioEssays

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“…This association does not establish direct interaction between the BCR and proton channel molecules but rather that both proteins are independently targeted to the same ordered lipid environment. Recent work (50) has shown that BCR activation (cross-linking) can induce the formation of relatively large signaling membrane platforms that are able to concentrate or exclude other membrane proteins based on their structure. The reported profile of membrane protein partitioning into these BCR-induced signaling platforms closely follows the one expected for ordered lipid cholesterol-dependent rafts (50).…”

Section: Discussionmentioning

confidence: 99%

“…Recent work (50) has shown that BCR activation (cross-linking) can induce the formation of relatively large signaling membrane platforms that are able to concentrate or exclude other membrane proteins based on their structure. The reported profile of membrane protein partitioning into these BCR-induced signaling platforms closely follows the one expected for ordered lipid cholesterol-dependent rafts (50). Therefore, it is highly likely that BCR cross-linking causes the accretion of smaller pre-existing domains rather than creating them de novo .…”

Section: Discussionmentioning

confidence: 99%

Human proton channels accumulate in cholesterol dependent membrane domains via direct interaction with stomatin

Ayuyan,

Cherny,

Chaves

et al. 2023

Preprint

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Many membrane proteins are modulated by cholesterol. Here we report strong effects of cholesterol depletion and restoration on the human voltage gated proton channel, hHV1 in excised patches but negligible effects in whole-cell configuration. Despite the presence of a putative cholesterol binding site, a CARC domain in the human voltage gated proton channel, hHV1, mutation of this domain did not affect cholesterol effects. The murine HV1 lacks a CARC sequence but displays similar cholesterol effects. These three results all argue against a direct effect of cholesterol on HV1. We propose that the data are explainable if HV1 preferentially associates with cholesterol-dependent lipid domains, or “rafts.” The rafts would be expected to concentrate in the membrane/glass interface and to be depleted from the electrically-accessible patch membrane. This idea is supported by evidence that HV1 channels can diffuse between seal and patch membranes when suction is applied. Suction pulls membrane constituents including HV1 into the patch. In whole-cell studies moderate osmotic stretch does not noticeably alter H+currents. Simultaneous truncation of the large intracellular N- and C-termini greatly attenuated the cholesterol effect, but C-truncation only did not. We conclude that the N-terminus is the region of attachment to lipid domains. Searching for abundant raft-associated molecules led to stomatin. Co-immunoprecipitation experiments showed that hHV1 binds to stomatin. The stomatin-mediated association of HV1 with cholesterol-dependent lipid domains provides a mechanism for cells to direct HV1 to subcellular location where it is needed, such as the phagosome in leukocytes.SignificanceMany membrane proteins are modulated by cholesterol. Here we explore effects of cholesterol on the human voltage-gated proton channel, hHV1. Although we find little evidence for a direct effect, cholesterol was found to exert a strong influence over H+current in excised membrane patches. These effects are explainable by hypothesizing that HV1 preferentially associates with cholesterol-dependent membrane lipid domains. We postulate that HV1 diffuses within the membrane and is concentrated in such domains that are anchored to the pipette glass by large membrane proteins. We find that HV1 co-immunoprecipitates with stomatin, a typical component of cholesterol dependent lipid domains. The association of HV1 with lipid domains provides a mechanism for directing HV1 to specific subcellular locations to perform specific functions.

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“…One key aspect of biological membranes is their compositional heterogeneity which plays a crucial role in cell functions. − Heterogeneous membrane domains dynamically form at the surface of biological membranes and play an important role in cell signaling as they locally concentrate lipids and membrane species in submicrometer areas whose properties differ from the rest of the membrane. The interaction of these domains with the actin cytoskeleton is clearly demonstrated: actin dynamics forms WASH domains at the surface of endosomes, induces nanodomains in membrane tubules leading to their scission, and controls protein clusters formation, , but the mechanisms by which the cytoskeleton affects lipid domain formation and stability remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Spatial Control of Arp2/3-Induced Actin Polymerization on Phase-Separated Giant Unilamellar Vesicles

Lopes dos Santos,

Malo,

Campillo

2023

ACS Synth. Biol.

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Deciphering the physical mechanisms underlying cell shape changes, while avoiding the cellular interior's complexity, involves the development of controlled basic biomimetic systems that imitate cell functions. In particular, the reconstruction of cytoskeletal dynamics on cell-sized giant unilamellar vesicles (GUVs) has allowed for the reconstituting of some cell-like processes in vitro. In fact, such a bottom-up strategy could be the basis for forming protocells able to reorganize or even move autonomously. However, reconstituting the subtle and controlled dynamics of the cytoskeleton−membrane interface in vitro remains an experimental challenge. Taking advantage of the lipidinduced segregation of an actin polymerization activator, we present a system that targets actin polymerization in specific domains of phaseseparated GUVs. We observe actin networks localized on Lo, Ld, or on both types of domains and the actin-induced deformation or reorganization of these domains. These results suggest that the system we have developed here could pave the way for future experiments further detailing the interplay between actin dynamics and membrane heterogeneities.

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Membrane phase separation drives responsive assembly of receptor signaling domains

Cited by 67 publications

References 62 publications

The asymmetric plasma membrane—A composite material combining different functionalities?

The asymmetric plasma membrane—A composite material combining different functionalities?

Human proton channels accumulate in cholesterol dependent membrane domains via direct interaction with stomatin

Spatial Control of Arp2/3-Induced Actin Polymerization on Phase-Separated Giant Unilamellar Vesicles

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