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Bidirectional transmembrane signaling by cytoplasmic domain separation in integrins

Minsoo Kim1, Christopher V Carman, Timothy A Springer

  • 1CBR Institute for Biomedical Research, Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.

Science (New York, N.Y.)
|September 23, 2003
PubMed

Insights

Integrins like LFA-1 undergo conformational changes, separating cytoplasmic domains during signaling. This mechanism explains how integrins transmit signals bidirectionally across cell membranes for crucial biological processes.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Integrins are critical plasma membrane receptors involved in development, immunity, wound healing, and metastasis.
  • The fundamental signaling mechanisms of integrins have remained largely unknown.
  • Integrin LFA-1 (alphaLbeta2) plays a key role in immune cell adhesion and trafficking.

Purpose of the Study:

  • To investigate cytoplasmic conformational changes in integrin LFA-1 within living cells.
  • To elucidate the molecular mechanism of bidirectional integrin signaling (inside-out and outside-in).
  • To understand how integrins transmit signals across the plasma membrane.

Main Methods:

  • Utilized fluorescence resonance energy transfer (FRET) to measure spatial proximity.
  • Engineered cyan fluorescent protein (CFP) and yellow fluorescent protein (YFP) fusion proteins for alphaL and beta2 cytoplasmic domains.
  • Observed conformational changes in resting and activated states of LFA-1 in living cells.

Main Results:

  • In resting state, the alphaL and beta2 cytoplasmic domains of LFA-1 were in close proximity.
  • Significant spatial separation of cytoplasmic domains occurred upon inside-out activation (increased adhesiveness).
  • Ligand binding (outside-in signaling) also induced substantial spatial separation of these domains.

Conclusions:

  • Bidirectional integrin signaling is mediated by the unclasping and separation of alpha and beta cytoplasmic domains.
  • This conformational change represents a novel mechanism for transmembrane signal transmission.
  • Understanding integrin conformational dynamics provides insights into immune responses and disease processes.

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