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Phosphoinositides and PIPs01:42

Phosphoinositides and PIPs

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Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
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Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the  phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and...
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Lipids as Anchors01:32

Lipids as Anchors

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In the plasma membrane, the lipids forming the bilayer can also act as an anchor to tether proteins to the membrane. The three main types of lipid anchors found in eukaryotes are – prenyl groups, fatty acyl groups, and glycosylphosphatidylinositol or GPI groups. Prenyl and fatty acyl groups act as anchors on the cytosolic surface of the membrane, whereas GPI anchors proteins on the extracellular side.
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The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
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Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
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Mechanism of Lamellipodia Formation

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Cells migrating in response to external stimuli form lamellipodia, which are thin membrane protrusions supported by a mesh of linked, branched, or unbranched actin filaments. These actin filaments interact with myosin motor proteins, creating the dynamic actomyosin complex within the cytoskeleton. Contractility, or the ability to generate contractile stress, is inherent to the actomyosin complex. It helps cells detect the stiffness of the surrounding ECM and exert contractile force for...
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PIP-on-a-chip: A Label-free Study of Protein-phosphoinositide Interactions
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Membrane-mediated dimerization potentiates PIP5K lipid kinase activity.

Scott D Hansen1,2, Albert A Lee3,4,5, Benjamin R Duewell1,2

  • 1Department of Chemistry and Biochemistry, University of Oregon, Eugene, United States.

Elife
|August 17, 2022
PubMed
Summary

Phosphatidylinositol 4-phosphate 5-kinases (PIP5K) regulate cell functions by binding PI(4,5)P2 lipids. Dimerization enhances PIP5K activity and sensing, creating a dynamic range of lipid kinase functions.

Keywords:
PI(4,5)P2PIP5Kbiochemistrychemical biologydimerizationkinasemembranemolecular biophysicsphosphatidylinositol phosphate lipidsstructural biology

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Fluorescence-Based Measurements of Phosphatidylserine/Phosphatidylinositol 4-Phosphate Exchange Between Membranes
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Single-molecule Super-resolution Imaging of Phosphatidylinositol 4,5-bisphosphate in the Plasma Membrane with Novel Fluorescent Probes
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Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Background:

  • Phosphatidylinositol 4-phosphate 5-kinases (PIP5K) are key enzymes producing phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] at the plasma membrane.
  • PI(4,5)P2 is crucial for cellular processes including receptor signaling, ion channel function, endocytosis, and actin dynamics.

Purpose of the Study:

  • To elucidate the regulatory mechanisms of PIP5K activity, focusing on lipid binding and kinase domain dimerization.
  • To investigate the relationship between PIP5K monomer-dimer equilibrium, membrane association, and catalytic efficiency.

Main Methods:

  • Studied PIP5K regulation through cooperative binding to PI(4,5)P2 lipids.
  • Investigated membrane-mediated dimerization of the PIP5K kinase domain.
  • Compared PIP5K behavior to constitutively dimeric PIP4K.

Main Results:

  • PIP5K exists in a monomer-dimer equilibrium in solution, unlike constitutively dimeric PIP4K.
  • PIP5K monomers bind PI(4,5)P2-rich membranes and dimerize in a protein density-dependent manner.
  • Dimerization enhances PIP5K catalytic efficiency via allosteric regulation and amplifies stochastic variations in kinase activity.

Conclusions:

  • PIP5K regulation involves cooperative lipid binding and membrane-induced dimerization.
  • Dimerization modulates PIP5K catalytic efficiency and stochastic behavior, enhancing cellular sensing mechanisms.
  • PIP5K membrane binding generates a wide dynamic range of lipid kinase activity responsive to PI(4,5)P2 and enzyme density.