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Related Experiment Videos

A phenylalanine zipper mediates APS dimerization.

Sirano Dhe-Paganon1, Eric D Werner, Masahiro Nishi

  • 1Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.

Nature Structural & Molecular Biology
|September 21, 2004
PubMed
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Adapter proteins APS, SH2-B, and LNK regulate signaling pathways. APS uses a novel phenylalanine zipper domain for homodimerization, enabling kinase activation without external signals.

Area of Science:

  • Molecular Biology
  • Protein Structure
  • Signal Transduction

Background:

  • Adapter proteins APS, SH2-B, and LNK are crucial regulators of receptor tyrosine kinase and JAK/STAT signaling pathways.
  • These proteins play key roles in cellular communication and growth modulation.

Purpose of the Study:

  • To investigate the mechanism of APS homodimerization.
  • To elucidate the structural basis of APS-mediated signaling modulation.
  • To identify novel protein-protein interaction motifs involved in kinase activation.

Main Methods:

  • Determined the crystal structure of the APS dimerization domain using bromide ion MAD phasing.
  • Analyzed the four-helix bundle structure and identified a 'phenylalanine zipper' motif.
  • Utilized a novel bridging yeast tri-hybrid assay to study kinase dimerization.

Related Experiment Videos

Main Results:

  • A conserved N-terminal domain mediates APS homodimerization via a four-helix bundle.
  • A novel 'phenylalanine zipper' motif, formed by interdigitated phenylalanine side chains, is critical for dimerization.
  • APS dimerizes JAK2, insulin receptor, and IGF1 receptor kinases through its SH2 and dimerization domains.

Conclusions:

  • The phenylalanine zipper domain provides a structural basis for APS homodimerization and kinase activation.
  • APS-mediated dimerization can activate tyrosine kinase activity independently of extracellular ligands.
  • This mechanism offers new insights into the regulation of receptor tyrosine kinase and JAK/STAT signaling.