Key Points
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Many changes in the structure and movements of cells depend on rearrangements of the cytoskeleton. The cytoskeleton is a dynamic system of protein filaments that is regulated by dozens of proteins that are, in turn, regulated by phosphoinositides. Phosphoinositides comprise a group of anionic lipids that are generated by phosphorylation of the phospholipid phosphatidylinositol. Actin filaments are the cytoskeletal elements that are most often altered by phosphoinositide signalling.
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Phosphoinositide-binding sites on cytoskeleton-regulating proteins are often flexible, cationic regions that allow large hinge-like transitions in the protein structure once the phosphoinositide, usually phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2), binds. The conformational change that is caused by phosphoinositides can either activate or inactivate the effects of the protein on the cytoskeleton or, in some cases, allow the protein to link the cytoskeleton to the cell membrane.
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Manipulating phosphoinositide levels in a cell — for example, by altering the expression of enzymes that form or remove them — causes changes in the overall actin architecture of the cell. These changes are consistent with data defining how individual actin-binding-protein functions depend on phosphoinositides in vivo. Some human diseases in which cells have an abnormal cytoskeleton are associated with mutations in phosphoinositide-remodelling enzymes.
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Soluble proteins that regulate cytoskeletal assembly do so by signalling to lipids like phosphoinositides, which are embedded in cell membranes. This allows local activation of force-producing reactions such as actin assembly to occur at the cytosol–membrane interface, where they are optimally positioned for cell motility.
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Biochemical data and imaging of fluorescent markers for specific phosphoinositides indicate that phosphoinositides are not uniformly distributed through cell membranes but, rather, are localized in small patches or in spatial gradients. Mechanisms to account for their localization include rapid local synthesis, clustering by interaction with cationic proteins, or a combination of hydrogen-bonding and physical interactions among the lipids themselves. Direct visualization of such hypothetical domains and the determination of how they relate to cholesterol-rich lipid rafts is an area that has seen much recent activity and controversy.
Abstract
Phosphorylated derivatives of the phospholipid phosphatidylinositol, or phosphoinositides, are implicated in many aspects of cell function. Binding of phosphoinositides that are localized within cell membranes to soluble protein ligands allows spatially selective regulation at the cytoplasm–membrane interface. Recently, studies that relate phosphoinositide production to membrane domains are converging with those that show effects of these lipids on the assembly of cellular actin, and are therefore linking membrane and cytoskeletal structures in new ways.
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Acknowledgements
U.L. would like to thank The Swedish National Science Research Council and The Swedish Cancer Society for long-standing financial support. P.A.J. would like to thank the US National Institute of Arthritis and Musculoskeletal and Skin Disease and the Fogarty International Center for financial support of work in this field.
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DATABASES
Interpro
OMIM
Swiss-Prot
Glossary
- PLECKSTRIN-HOMOLOGY (PH) DOMAIN
-
A sequence of 100 amino acids that is present in many signalling molecules and binds to phosphoinositides. Pleckstrin is a protein of unknown function that was originally identified in platelets. It is a principal substrate of protein kinase C.
- RHO-FAMILY GTPases
-
Ras-related GTPases that are involved in controlling the polymerization of actin.
- LIPID RAFTS
-
Lateral aggregates of cholesterol and sphingomyelin that are thought to occur in the plasma membrane.
- RUFFLES
-
Processes that are formed by the movement of lamellipodia that are in the dynamic process of folding back onto the cell body from which they previously extended.
- GROWTH CONE
-
Motile tip of the axon or dendrite of a growing nerve cell, which spreads out into a large cone-shaped appendage.
- FOCAL-ADHESION COMPLEX
-
Focal adhesions are cellular structures that link the extracellular matrix on the outside of the cell, through integrin receptors, to the actin cytoskeleton inside the cell.
- PHAGOCYTOSIS
-
An actin-dependent process by which cells engulf external particulate material by extension and fusion of pseudopods.
- FRET
-
(fluorescence resonance energy transfer). The fluorescence energy that is transferred from one fluor excites a neighbouring fluor that then re-emits the energy at a third wavelength. Transfer occurs only if the two fluors are close, so FRET can be used to monitor real-time protein–protein interactions in living cells.
- FILOPODIA
-
Thin cellular processes containing long, unbranched, parallel bundles of actin filaments.
- PX DOMAIN
-
(phox-homology domain). A lipid- and protein-interaction domain that consists of 100–130 amino acids and is defined by sequences that are found in two components of the phagocyte NADPH oxidase (phox) complex.
- EPSIN AMINO (N)-TERMINAL HOMOLOGY DOMAIN
-
(ENTH). A phospholipid-binding motif with high affinity for PtdIns(4,5)P2.
- NUCLEAR MAGNETIC RESONANCE
-
(NMR). A technique used to determine the content, purity and molecular structure of a sample. This method is based on the fact that some atomic nuclei have a magnetic moment. When these nuclei are placed in a magnetic field and are simultaneously exposed to electromagnetic radiation, they change their energy state and absorb energy.
- CIRCULAR DICHROISM
-
An optical method measuring differential effects on light of different polarization directions to quantify the amount of α-helical and β-stranded structures within proteins.
- Z-BAND
-
A region of muscle sarcomere to which the plus ends of actin filaments are attached. It appears as a dark transverse line in micrographs.
- SARCOMERE
-
The structure within a muscle cell where actin and myosin filaments overlap to produce the movements that are required for muscle contraction. Proteins such as α-actinin were first described in these structures as proteins required to bind actin filaments in parallel arrays. Similar biochemical interactions between actin and actin-binding proteins also occur in non-muscle cells.
- β-STRAND
-
An element of protein secondary structure. Hydrogen bonds between the backbones of the same or different polypeptides stabilize arrays of parallel chains that can form larger elements resembling sheets.
- α-HELIX
-
An element of protein secondary structure in which hydrogen bonds along the backbone of a single polypeptide cause the chain to form a right-handed helix.
- FRAP
-
(fluorescence recovery after photobleaching). A live-cell imaging technique used to study the mobility of fluorescent molecules. A pulse of high intensity light is used to irreversibly photobleach a population of fluorophores in a target region. Recovery of fluorescence in the bleached region represents movement of fluorophores into that region.
- OUTER PLASMA-MEMBRANE LEAFLET
-
A lipid layer that faces the outside of the cell.
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Janmey, P., Lindberg, U. Cytoskeletal regulation: rich in lipids. Nat Rev Mol Cell Biol 5, 658–666 (2004). https://doi.org/10.1038/nrm1434
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DOI: https://doi.org/10.1038/nrm1434
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