PX Domains

Cheever, Matthew L.; Overduin, Michael

doi:10.1002/3527603611.ch19

Cited by 5 publications

(8 citation statements)

References 62 publications

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“…The remaining PX domains had complete 3D structures from previous NMR spectroscopy and X-ray crystallography studies. As expected, the PX structures converged well and display a common fold and membrane binding area (Cheever and Overduin, 2004; Figure 2). This common structural framework provides a straightforward basis for comparing the various lipid binding and regulatory properties.…”

Section: Structural Basis Of Membrane Bindingsupporting

confidence: 78%

Phosphoinositide Recognition Sites Are Blocked by Metabolite Attachment

Kervin

Wiseman

Overduin

2021

Front. Cell Dev. Biol.

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Membrane readers take part in trafficking and signaling processes by localizing proteins to organelle surfaces and transducing molecular information. They accomplish this by engaging phosphoinositides (PIs), a class of lipid molecules which are found in different proportions in various cellular membranes. The prototypes are the PX domains, which exhibit a range of specificities for PIs. Our meta-analysis indicates that recognition of membranes by PX domains is specifically controlled by modification of lysine and arginine residues including acetylation, hydroxyisobutyrylation, glycation, malonylation, methylation and succinylation of sidechains that normally bind headgroups of phospholipids including organelle-specific PI signals. Such metabolite-modulated residues in lipid binding elements are named MET-stops here to highlight their roles as erasers of membrane reader functions. These modifications are concentrated in the membrane binding sites of half of all 49 PX domains in the human proteome and correlate with phosphoregulatory sites, as mapped using the Membrane Optimal Docking Area (MODA) algorithm. As these motifs are mutated and modified in various cancers and the responsible enzymes serve as potential drug targets, the discovery of MET-stops as a widespread inhibitory mechanism may aid in the development of diagnostics and therapeutics aimed at the readers, writers and erasers of the PI code.

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Section: Structural Basis Of Membrane Bindingsupporting

confidence: 78%

Phosphoinositide Recognition Sites Are Blocked by Metabolite Attachment

Kervin

Wiseman

Overduin

2021

Front. Cell Dev. Biol.

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“…While there has been longstanding interest in membrane proteins, the importance of the lipid constituents has more recently begun to attract interest, − in part because the action of the proteins is influenced by the local mechanical properties (fluidity) of the membrane, − the charge of the lipid headgroups, and specific interactions with the headgroups. − For example, proteins may be preferentially located in less-fluid or more-fluid domains , or may be surrounded by an annulus of a particular lipid type . Lipids of various types are also essential in cell-signaling processes. ,, To understand fully the role of lipids in membrane function, it is necessary to build a picture of how the lipids’ molecular structures affect the properties of the membranes they form. For this undertaking, it is common to use model systems where the composition and environment can be more precisely controlled, − such as vesicles, monolayers, and supported bilayers. , A range of structural probes may then be employed, including X-ray − and neutron − scattering techniques, vibrational spectroscopies, − and imaging methods, − inter alia.…”

Section: Introductionmentioning

confidence: 99%

Effect of Anionic Lipids on Mammalian Plasma Cell Membrane Properties

et al. 2023

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The effect of lipid composition on models of the inner leaflet of mammalian cell membranes has been investigated. Grazing incidence X-ray diffraction and X-ray and neutron reflectivity have been used to characterize lipid packing and solvation, while electrochemical and infrared spectroscopic methods have been employed to probe phase behavior in an applied electric field. Introducing a small quantity of the anionic lipid dimyristoylphosphatidylserine (DMPS) into bilayers of zwitterionic dimyristoylphosphatidylethanolamine (DMPE) results in a significant change in the bilayer response to an applied field: the tilt of the hydrocarbon chains increases before returning to the original tilt angle on detachment of the bilayer. Equimolar mixtures, with slightly closer chain packing, exhibit a similar but weaker response. The latter also tend to incorporate more solvent during this electrochemical phase transition, at levels similar to those of pure DMPS. Reflectivity measurements reveal greater solvation of lipid layers for DMPS > 30 mol %, matching the greater propensity for DMPS-rich bilayers to incorporate water. Taken together, the data indicate that the range of 10–35 mol % DMPS provides optimum bilayer properties (in flexibility and function as a barrier), which may explain why the DMPS content of cell membranes tends to be found within this range.

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“…The basis of the membrane is a lipid bilayer containing a variety of receptors, signaling molecules, and functional proteins. There is a wide variety of lipids in natural cell membranes, and the membrane composition varies not only between species but also between cell types in an organism and between different membrane types within a cell. , The lipid components of the bilayer have multiple structural and functional roles, which are now beginning to be appreciated. , For example, the composition modulates local membrane tension, which can be important for the action of proteins, and some lipids have specific functional group interactions with proteins, − while some are involved in cell-signaling processes . The lipid bilayer is a complex mixture of saturated and unsaturated lipids, lipids of different headgroups, and sterols.…”

Section: Introductionmentioning

confidence: 99%

“…1 , 2 The lipid components of the bilayer have multiple structural and functional roles, which are now beginning to be appreciated. 3 , 4 For example, the composition modulates local membrane tension, which can be important for the action of proteins, 5 and some lipids have specific functional group interactions with proteins, 6 − 8 while some are involved in cell-signaling processes. 3 The lipid bilayer is a complex mixture of saturated and unsaturated lipids, lipids of different headgroups, and sterols.…”

Section: Introductionmentioning

confidence: 99%

Influence of the Lipid Backbone on Electrochemical Phase Behavior

et al. 2022

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Sphingolipids are an important class of lipids found in mammalian cell membranes with important structural and signaling roles. They differ from another major group of lipids, the glycerophospholipids, in the connection of their hydrocarbon chains to their headgroups. In this study, a combination of electrochemical and structural methods has been used to elucidate the effect of this difference on sphingolipid behavior in an applied electric field. N-Palmitoyl sphingomyelin forms bilayers of similar coverage and thickness to its close analogue di-palmitoyl phosphatidylcholine. Grazing incidence diffraction data show slightly closer packing and a smaller chain tilt angle from the surface normal. Electrochemical IR results at low charge density show that the difference in tilt angle is retained on deposition to form bilayers. The bilayers respond differently to increasing electric field strength: chain tilt angles increase for both molecules, but sphingomyelin chains remain tilted as field strength is further increased. This behavior is correlated with disruption of the hydrogen-bonding network of small groups of sphingomyelin molecules, which may have significance for the behavior of molecules in lipid rafts in the presence of strong fields induced by ion gradients or asymmetric distribution of charged lipids.

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PX Domains

Cited by 5 publications

References 62 publications

Phosphoinositide Recognition Sites Are Blocked by Metabolite Attachment

Phosphoinositide Recognition Sites Are Blocked by Metabolite Attachment

Effect of Anionic Lipids on Mammalian Plasma Cell Membrane Properties

Influence of the Lipid Backbone on Electrochemical Phase Behavior

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