Identification of novel sphingolipid-binding motifs in mammalian membrane proteins

Björkholm, Patrik; Ernst, Andreas; Hacke, Moritz; Wieland, Felix; Brügger, Britta; Heijne, Gunnar von

doi:10.1016/j.bbamem.2014.04.026

Cited by 49 publications

(40 citation statements)

References 20 publications

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“…The list of sphingolipid-binding proteins is expanding, but only relatively few sphingolipid-binding motifs have been identified [129–131]. SM has been shown to regulate the activity of the Kv2.1 channel by interacting with the helix-turn-helix motif found in the S3b and S4 voltage-sensing domains of the channel in oocytes [113,116].…”

Section: Brain Ion Channels and Receptors In Microdomainsmentioning

confidence: 99%

Sphingolipids: membrane microdomains in brain development, function and neurological diseases

Olsen¹,

Færgeman²

2017

Open Biol.

253

199

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Sphingolipids are highly enriched in the nervous system where they are pivotal constituents of the plasma membranes and are important for proper brain development and functions. Sphingolipids are not merely structural elements, but are also recognized as regulators of cellular events by their ability to form microdomains in the plasma membrane. The significance of such compartmentalization spans broadly from being involved in differentiation of neurons and synaptic transmission to neuronal–glial interactions and myelin stability. Thus, perturbations of the sphingolipid metabolism can lead to rearrangements in the plasma membrane, which has been linked to the development of various neurological diseases. Studying microdomains and their functions has for a long time been synonymous with studying the role of cholesterol. However, it is becoming increasingly clear that microdomains are very heterogeneous, which among others can be ascribed to the vast number of sphingolipids. In this review, we discuss the importance of microdomains with emphasis on sphingolipids in brain development and function as well as how disruption of the sphingolipid metabolism (and hence microdomains) contributes to the pathogenesis of several neurological diseases.

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Section: Brain Ion Channels and Receptors In Microdomainsmentioning

confidence: 99%

Sphingolipids: membrane microdomains in brain development, function and neurological diseases

Olsen¹,

Færgeman²

2017

Open Biol.

253

199

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“…Importantly, the DAG-C1 affinities (1/K d ) of the two natural lipids SAG and SOG differed by one order of magnitude, indicating a clear side-chain specificity of the DAG binding domain. This finding demonstrates that species-specific lipid-protein interactions can occur within biological membranes, a hypothesis that has been frequently put forward (12), but only rarely experimentally tested (32). Taken together, the ability to quantitatively determine lipid-protein affinities and dynamics for individual lipid species allows to test key hypotheses in membrane biology, for example the notion that lipid structural diversity serves as a means for encoding information during cellular signalling events.…”

Section: Resultsmentioning

confidence: 60%

Addressing lipid structural diversity in signalling: Photochemical probes for live-cell lipid biochemistry

Schuhmacher

Grasskamp

Wagner

et al. 2019

Preprint

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18Every cell produces thousands of distinct lipid species, but methodology for studying the biological 19 roles of individual lipids is insufficient. Using the example of diacylglycerols, prominent second 20 messengers, we here investigate whether lipid chemical diversity can provide a basis for cellular 21 signal specification. We developed novel photo-caged lipid probes, which allow acute manipulation 22 of distinct diacylglycerol species in the plasma membrane. Combining uncaging experiments with 23 mathematical modelling enabled the determination of binding constants for diacylglycerol-protein 24 interactions and kinetic parameters for diacylglycerol transbilayer movement and turnover in 25 quantitative live-cell experiments. Strikingly, we find that affinities and kinetics vary by orders of 26 magnitude due to diacylglycerol structural diversity. These differences are sufficient to explain 27 differential recruitment of diacylglycerol binding proteins and thus differing downstream 28 phosphorylation patterns. Our approach represents a generally applicable method for elucidating the 29 biological function of single lipid species on subcellular scales. 30 Intriguingly, a growing body of evidence suggests that changes in the levels of individual lipid species 43 rather than entire lipid classes determine cellular signalling outcome. For instance, early studies 44 reported that activation of individual cell surface receptors leads to the formation of molecularly 45 distinct patterns of diacylglycerol (DAG) species during signal transduction (13-15), suggesting that 46 crucial information could be encoded in the molecular spectrum of signalling lipids generated. 47Supporting this notion, drastically altered levels of distinct lipid species were correlated with cellular 48 processes, e.g. the increase of a phosphatidic acid ether lipid during cytokinesis (16) or the reciprocal 49 regulation of ceramide species during toll-like receptor signaling in innate immunity (17). DAGs 50 appear to be prime targets to study the importance of lipid heterogeneity in cell signalling, as they act 51 as second messengers at the plasma membrane and function in many cellular processes, including 52 insulin signalling, ion channel regulation and neurotransmitter release (18, 19). Many of these 53 processes involve effector proteins such as protein kinase C (PKC) isoforms, which are recruited to 54 cellular membranes by DAG binding to their C1 domains (20). Faithful process initiation thus 55 requires the activation of a subset of DAG effector proteins in the presence of others as observed 56 during the formation of the immunological synapse (21), but the molecular mechanisms of such 57 specific recruitment events are not well understood. Here, specificity could be provided by 58 differential activation of effectors by structurally distinct DAG species which recruit DAG binding 59 proteins due to differences in lipid-protein affinities, local lipid densities and lifetimes. Determining 60 these parameters requires quantitative experim...

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“…Recently, a sphingolipid motif was found in the transmembrane protein p24, which is involved in vesicular transport in the early secretory pathway (Contreras et al, 2012). Later a number of membrane proteins with a similar motif have been found (Bjorkholm et al, 2014), indicating that such lipid binding may be a relatively common event. The binding of lipids to proteins may regulate their function, as for example in the case of p24, but possibly lipids bound to the surface of transmembrane proteins could influence how they partition between different lipid environments in much the same way as palmitoylation has been reported to do.…”

Section: Protein Partitioning Between Disordered and Ordered Membranementioning

confidence: 98%

Lipid-protein interplay and lateral organization in biomembranes

Nyholm

2015

Chemistry and Physics of Lipids

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Identification of novel sphingolipid-binding motifs in mammalian membrane proteins

Cited by 49 publications

References 20 publications

Sphingolipids: membrane microdomains in brain development, function and neurological diseases

Sphingolipids: membrane microdomains in brain development, function and neurological diseases

Addressing lipid structural diversity in signalling: Photochemical probes for live-cell lipid biochemistry

Lipid-protein interplay and lateral organization in biomembranes

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