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Related Experiment Videos

Bidirectional transmembrane modulation of integrin alphaIIbbeta3 conformations.

T M Leisner1, J D Wencel-Drake, W Wang

  • 1Department of Pharmacology, University of Illinois, Chicago, Illinois 60612, USA.

The Journal of Biological Chemistry
|April 23, 1999
PubMed
Summary

Platelet activation involves bidirectional signaling through alphaIIbbeta3 integrins. This study reveals how ligand binding triggers conformational changes, linking extracellular and intracellular domains for platelet function.

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Medicine

Background:

  • Platelet activation by stimuli like thrombin and ADP initiates inside-out signaling.
  • This signaling changes the alphaIIbbeta3 integrin conformation, enabling fibrinogen binding.
  • Ligand binding to alphaIIbbeta3 also triggers outside-in signaling and exposes neoepitopes (LIBS).

Purpose of the Study:

  • To elucidate the mechanism of bidirectional transmembrane signaling in alphaIIbbeta3 integrins.
  • To investigate the role of extracellular ligand binding in initiating transmembrane conformational changes.
  • To identify the specific cytoplasmic regions involved in alphaIIbbeta3 signaling.

Main Methods:

  • Development and use of a novel anti-LIBS cytoplasmic 1 (LIBScyt1) monoclonal antibody.

Related Experiment Videos

  • Analysis of conformational changes in alphaIIbbeta3 upon extracellular ligand binding.
  • Site-directed mutagenesis of the alphaIIb cytoplasmic sequence (P998A/P999A) to assess functional consequences.

    • Main Results:

    • Extracellular ligand binding to alphaIIbbeta3 induces a transmembrane conformational change.
    • The LIBScyt1 epitope is exposed in the alphaIIb cytoplasmic sequence (Lys994-Asp1003).
    • A point mutation (P998A/P999A) resulted in constitutive alphaIIbbeta3 activity and fibrinogen-dependent cell aggregation.

    Conclusions:

    • The extracellular ligand-binding site and the cytoplasmic LIBS epitope of alphaIIbbeta3 are conformationally and functionally coupled.
    • Bidirectional modulation of alphaIIbbeta3 conformation across the cell membrane is crucial for integrin signaling.
    • These findings provide insights into the molecular mechanisms of platelet activation and aggregation.