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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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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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Cotranslational Protein Translocation01:20

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Translocation of proteins across membranes is an ancient process that occurs even in bacteria and archaebacteria. In fact, the components of the translocation machinery are still conserved between prokaryotes and eukaryotes.
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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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The organelle-specific signaling sequences direct proteins synthesized in the cytosol to their final destination like ER, mitochondria, peroxisomes, etc. Some of the proteins directed to ER are then trafficked via vesicles to other organelles within the cell or the extracellular environment through the Golgi complex. For example, the rough ER synthesizes soluble proteins for transportation to the lysosomes or secretion out of the cell. It can also synthesize transmembrane proteins that can...
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Related Experiment Video

Updated: Sep 22, 2025

Identification of Inositol Phosphate or Phosphoinositide Interacting Proteins by Affinity Chromatography Coupled to Western Blot or Mass Spectrometry
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Rendezvous with PI(3,5)P2 - A rapalog gets caught opening TRPML1.

Taufiq Rahman1, Sandip Patel2

  • 1Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, United Kingdom.

Cell Calcium
|May 21, 2022
PubMed
Summary

New structures reveal how the TRPML1 channel integrates two activators, PI(3,5)P2 and temsirolimus, at distinct sites for cooperative function. This provides molecular insights into TRPML1 channel regulation.

Keywords:
AllostericCa(2+) channelsLysosomePI(3,5)P(2)RapamycinTRPML1Temsirolimus

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Area of Science:

  • Molecular biology
  • Biophysics
  • Cell biology

Background:

  • TRPML1 is a cation channel located in endolysosomes.
  • It plays a crucial role in cellular processes.
  • TRPML1 is activated by phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) and synthetic agonists like rapamycin.

Purpose of the Study:

  • To elucidate the molecular mechanism of TRPML1 activation by multiple agonists.
  • To provide high-resolution structural insights into TRPML1-agonist interactions.

Main Methods:

  • High-resolution cryo-electron microscopy (cryo-EM).
  • Structural analysis of TRPML1 in complex with PI(3,5)P2 and temsirolimus.

Main Results:

  • Determined cryo-EM structures of TRPML1 bound to both PI(3,5)P2 and temsirolimus.
  • Revealed that these agonists bind to distinct, distal sites on the channel.
  • Demonstrated cooperative binding and activation, suggesting an integrated regulatory mechanism.

Conclusions:

  • The findings provide a molecular basis for how TRPML1 integrates signals from different activators.
  • Understanding this cooperative mechanism is key to deciphering TRPML1 channel function in various physiological and pathological contexts.