The Enigmatic Role of Lipids in Cilia Signaling

Nechipurenko, Inna V.

doi:10.3389/fcell.2020.00777

Cited by 23 publications

(14 citation statements)

References 122 publications

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“…for cholesterol dependent differences in protein regulation. PC2 and PTCH1 localise to the primary cilia, where the abundance of accessible membrane cholesterol is highly regulated 78 . Changes in cilia cholesterol levels coincide with activation levels of key signalling pathways and to the subcellular localisation of PTCH1 75,79 .…”

Section: Discussionmentioning

confidence: 99%

Relative Affinities of Protein-Cholesterol Interactions from Equilibrium Molecular Dynamics Simulations

Ansell

Curran

Horrell

et al. 2021

Preprint

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Specific interactions of lipids with membrane proteins contribute to protein stability and function. Multiple lipid interactions surrounding a membrane protein are often identified in molecular dynamics (MD) simulations and are, increasingly, resolved in cryo-EM densities. Determining the relative importance of specific interaction sites is aided by determination of lipid binding affinities by experimental or simulation methods. Here, we develop a method for determining protein-lipid binding affinities from equilibrium coarse-grained MD simulations using binding saturation curves, designed to mimic experimental protocols. We apply this method to directly obtain affinities for cholesterol binding to multiple sites on a range of membrane proteins and compare our results with free energies obtained from density-based equilibrium methods and with potential of mean force calculations, getting good agreement with respect to the ranking of affinities for different sites. Thus, our binding saturation method provides a robust, high-throughput alternative for determining the relative consequence of individual sites seen in e.g. cryo-EM derived membrane protein structures surrounded by a plethora of ancillary lipid densities.

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Section: Discussionmentioning

confidence: 99%

Relative Affinities of Protein-Cholesterol Interactions from Equilibrium Molecular Dynamics Simulations

Ansell

Curran

Horrell

et al. 2021

Preprint

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“…One conceivable explanation may be that HDLs are able to evoke hyperactivated motility in the sperm flagellum simply by modifying the lipid composition following cholesterol efflux. Lipids have recently emerged as critical regulators of flagella or cilia function, whereby the distinct lipid composition and compartmentalization of the ciliary membrane is known to be essential for ion channel activity and transduction of cilia-based signaling cascades [ 66 ]. Since the trigger and maintenance of hyperactivation is dependent on the influx of Ca 2+ through designated channels, like CatSper [ 67 ], the relationship between lipid composition and ion channel activity could potentially explain the dual action of HDLs in ram spermatozoa.…”

Section: Discussionmentioning

confidence: 99%

HDL mediates reverse cholesterol transport from ram spermatozoa and induces hyperactivated motility

Bernecic

Graaf

Leahy

et al. 2021

Biology of Reproduction

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Reverse Cholesterol Transport or cholesterol efflux is part of an extensive plasma membrane remodelling process in spermatozoa that is imperative for fertilisation. For ram spermatozoa, sheep serum is well known to support in vitro fertilisation (IVF), but knowledge of its explicit role is limited. Though, it is postulated to elicit cholesterol efflux owing to the presence of high density lipoproteins (HDLs) that interact with transmembrane cholesterol transporters, such as ATP-binding cassette transporter A1 (ABCA1) and scavenger receptor class B, type I (SR-BI). In this study, we report that both sheep serum and HDLs were able to elicit cholesterol efflux alone by up to 20–40% (as measured by the BODIPY-cholesterol assay). Furthermore, when the antagonists glibenclamide and valspodar were used to inhibit the function of ABCA1 and SR-BI or ABCA1 alone, respectively, cholesterol efflux was only marginally reduced (8–15)%. Nevertheless, it is likely that in ram spermatozoa, a specific facilitated pathway of cholesterol efflux is involved in the interaction between cholesterol acceptors and transporters. Interestingly, exposure to HDLs also induced hyperactivated motility, another critical event required for successful fertilisation. Taken together, this study details the first report of the dual action of HDLs on ram spermatozoa, providing both an insight into the intricacy of events leading up to fertilisation in vivo as well as demonstrating the possible application of HDL supplementation in media for IVF.

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“…Primary cilia also regulate adipogenesis through omega-3 fatty acid-activated FFAR4/GPR120 and desert hedgehog-activated smoothened [ 58 , 59 ]. However, the relationship between primary cilia and lipid rafts in the regulation of Akt signalling remains largely unknown [ 26 , 60 ].…”

Section: Primary Cilia Regulate Lipid Raft Dynamics Related To Ir–akt Signalling In Adipogenesismentioning

confidence: 99%

Primary cilia and lipid raft dynamics

et al. 2021

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Primary cilia, antenna-like structures of the plasma membrane, detect various extracellular cues and transduce signals into the cell to regulate a wide range of functions. Lipid rafts, plasma membrane microdomains enriched in cholesterol, sphingolipids and specific proteins, are also signalling hubs involved in a myriad of physiological functions. Although impairment of primary cilia and lipid rafts is associated with various diseases, the relationship between primary cilia and lipid rafts is poorly understood. Here, we review a newly discovered interaction between primary cilia and lipid raft dynamics that occurs during Akt signalling in adipogenesis. We also discuss the relationship between primary cilia and lipid raft-mediated Akt signalling in cancer biology. This review provides a novel perspective on primary cilia in the regulation of lipid raft dynamics.

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The Enigmatic Role of Lipids in Cilia Signaling

Cited by 23 publications

References 122 publications

Relative Affinities of Protein-Cholesterol Interactions from Equilibrium Molecular Dynamics Simulations

Relative Affinities of Protein-Cholesterol Interactions from Equilibrium Molecular Dynamics Simulations

HDL mediates reverse cholesterol transport from ram spermatozoa and induces hyperactivated motility

Primary cilia and lipid raft dynamics

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