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Flow-enhanced adhesion regulated by a selectin interdomain hinge.

Jizhong Lou1, Tadayuki Yago, Arkadiusz G Klopocki

  • 1Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA.

The Journal of Cell Biology
|September 27, 2006
PubMed
Summary
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Modifying L-selectin flexibility lowers the shear threshold for leukocyte adhesion. This enhances tethering and strengthens rolling interactions by creating longer-lasting catch bonds, crucial for immune cell trafficking.

Area of Science:

  • Cellular mechanics
  • Immunology
  • Biophysics

Background:

  • Leukocyte adhesion and rolling on vascular surfaces are mediated by L-selectin, requiring a threshold shear force.
  • Flow-enhanced tethering is governed by transport mechanisms, while flow-enhanced rolling relies on force-dependent catch bonds.

Purpose of the Study:

  • To investigate how altering L-selectin flexibility impacts leukocyte adhesion dynamics.
  • To elucidate the mechanisms behind flow-enhanced tethering and rolling through modifications of L-selectin's interdomain hinge.

Main Methods:

  • Utilized selectin crystal structures, molecular dynamics simulations, and site-directed mutagenesis.
  • Employed single-molecule force and kinetics experiments, Monte Carlo modeling, and flow chamber adhesion studies.

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Main Results:

  • Eliminating a hydrogen bond increased L-selectin hinge flexibility, reducing the shear threshold for adhesion.
  • Increased rotational diffusion enhanced the on-rate of tethering, while augmented catch bonds with longer lifetimes improved rolling.
  • Ligand sliding across the L-selectin interface promoted rebinding, explaining catch bond mechanisms.

Conclusions:

  • Allosteric changes in L-selectin, remote from the ligand-binding site, regulate both bond formation and dissociation.
  • Modulating L-selectin flexibility offers a mechanism to control leukocyte-ligand interactions under flow conditions.