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Clusters of bioactive compounds target dynamic endomembrane networks in vivo

Academic Article
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Overview

authors

  • Drakakaki, G.
  • Robert, S.
  • Szatmari, A. M.
  • Brown, M. Q.
  • Nagawa, S.
  • Van Damme, D.
  • Leonard, M.
  • Yang, Z. B.
  • Girke, T.
  • Schmid, Sandra
  • Russinova, E.
  • Friml, J.
  • Raikhel, N. V.
  • Hicks, G. R.

publication date

  • October 2011

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Endomembrane trafficking relies on the coordination of a highly complex, dynamic network of intracellular vesicles. Understanding the network will require a dissection of cargo and vesicle dynamics at the cellular level in vivo. This is also a key to establishing a link between vesicular networks and their functional roles in development. We used a high-content intracellular screen to discover small molecules targeting endomembrane trafficking in vivo in a complex eukaryote, Arabidopsis thaliana. Tens of thousands of molecules were prescreened and a selected subset was interrogated against a panel of plasma membrane (PM) and other endomembrane compartment markers to identify molecules that altered vesicle trafficking. The extensive image dataset was transformed by a flexible algorithm into a marker-by-phenotype-by-treatment time matrix and revealed groups of molecules that induced similar subcellular fingerprints (clusters). This matrix provides a platform for a systems view of trafficking. Molecules from distinct clusters presented avenues and enabled an entry point to dissect recycling at the PM, vacuolar sorting, and cell-plate maturation. Bioactivity in human cells indicated the value of the approach to identifying small molecules that are active in diverse organisms for biology and drug discovery.

subject areas

  • Algorithms
  • Arabidopsis
  • Biological Transport
  • Cell Membrane
  • Cells, Cultured
  • Cluster Analysis
  • Fluorescent Antibody Technique
  • Green Fluorescent Proteins
  • HeLa Cells
  • Humans
  • Microscopy, Confocal
  • Molecular Structure
  • Seedlings
  • Small Molecule Libraries
  • Time-Lapse Imaging
  • Tobacco
  • Transport Vesicles
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Research

keywords

  • chemical genomics
  • endosidin
  • endosome
  • high content screen
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Identity

PubMed Central ID

  • PMC3203817

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1108581108

PubMed ID

  • 22006339
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Additional Document Info

start page

  • 17850

end page

  • 17855

volume

  • 108

issue

  • 43

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