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Related Concept Videos

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.
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
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IP3/DAG Signaling Pathway01:11

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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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PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

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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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Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

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Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
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Amplifying Signals via Second Messengers01:15

Amplifying Signals via Second Messengers

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Many receptor binding ligands are hydrophilic; they do not cross the cell membrane but bind to cell-surface receptors. Thus, their message must be relayed by second messengers present in the cell cytoplasm. There are several second messenger pathways, each with its own way of relaying information. For example, the G protein-coupled receptors can activate both phosphoinositol and cyclic AMP (cAMP) second messenger pathways. The phosphoinositol pathway is active when the receptor induces...
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Calmodulin-dependent Signaling01:16

Calmodulin-dependent Signaling

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Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
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Related Experiment Video

Updated: Oct 1, 2025

Identification of Inositol Phosphate or Phosphoinositide Interacting Proteins by Affinity Chromatography Coupled to Western Blot or Mass Spectrometry
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Identification of Inositol Phosphate or Phosphoinositide Interacting Proteins by Affinity Chromatography Coupled to Western Blot or Mass Spectrometry

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Structural basis of phosphatidylinositol 3-kinase C2α function.

Wen-Ting Lo1, Yingyi Zhang2,3,4, Oscar Vadas5

  • 1Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany. lo@fmp-berlin.de.

Nature Structural & Molecular Biology
|March 8, 2022
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Summary

Structural insights into Phosphatidylinositol 3-kinase type 2α (PI3KC2α) reveal a lipid-induced activation mechanism. This study provides a model for class II PI3K activation and scaffolding, aiding targeted therapeutic development.

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PIP-on-a-chip: A Label-free Study of Protein-phosphoinositide Interactions
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Radiolabeling and Quantification of Cellular Levels of Phosphoinositides by High Performance Liquid Chromatography-coupled Flow Scintillation
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Identification of Inositol Phosphate or Phosphoinositide Interacting Proteins by Affinity Chromatography Coupled to Western Blot or Mass Spectrometry
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PIP-on-a-chip: A Label-free Study of Protein-phosphoinositide Interactions
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Radiolabeling and Quantification of Cellular Levels of Phosphoinositides by High Performance Liquid Chromatography-coupled Flow Scintillation
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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Phosphatidylinositol 3-kinase type 2α (PI3KC2α) is vital for cellular processes like endocytosis and mitosis.
  • The structural basis for PI3KC2α's diverse functions remains largely unknown.
  • Class II PI3Ks are critical but structurally undercharacterized enzyme family.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying PI3KC2α activation and function.
  • To determine the high-resolution structures of PI3KC2α in different functional states.
  • To provide a structural model for the activation of class II PI3K family members.

Main Methods:

  • High-resolution X-ray crystallography.
  • Cryo-electron microscopy (cryo-EM) at 4.4-Å resolution.
  • Structural analysis of active and inactive PI3KC2α conformations.

Main Results:

  • Revealed a lipid-induced activation mechanism involving domain repositioning in PI3KC2α.
  • Determined crystal and cryo-EM structures of PI3KC2α, detailing active and inactive states.
  • Identified a PI3KC2α-specific helical bundle domain crucial for mitotic spindle scaffolding.

Conclusions:

  • The findings provide a mechanistic understanding of PI3KC2α activation at membranes.
  • The study offers a structural blueprint for class II PI3K family activation.
  • Results facilitate the development of targeted class II PI3K inhibitors for biomedical applications.