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The Center for Blood Research, and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115
Two mechanisms have been proposed for
regulating rolling velocities on selectins. These are (a)
the intrinsic kinetics of bond dissociation, and (b) the
reactive compliance, i.e., the susceptibility of the bond
dissociation reaction to applied force. To determine
which of these mechanisms explains the 7.5-11.5-fold faster rolling of leukocytes on L-selectin than on E- and
P-selectins, we have compared the three selectins by examining the dissociation of transient tethers. We find
that the intrinsic kinetics for tether bond dissociation
are 7-10-fold more rapid for L-selectin than for E- and
P-selectins, and are proportional to the rolling velocities through these selectins. The durations of pauses
during rolling correspond to the duration of transient
tethers on low density substrates. Moreover, applied
force increases dissociation kinetics less for L-selectin
than for E- and P-selectins, demonstrating that reactive
compliance is not responsible for the faster rolling through L-selectin. Further measurements provide a
biochemical and biophysical framework for understanding the molecular basis of rolling. Displacements
of tethered cells during flow reversal, and measurements of the distance between successive pauses during rolling provide estimates of the length of a tether and
the length of the adhesive contact zone, and suggest
that rolling occurs with as few as two tethers per contact zone. Tether bond lifetime is an exponential function of the force on the bond, and the upper limit for
the tether bond spring constant is of the same order of
magnitude as the estimated elastic spring constant of
the lectin-EGF unit. Shear uniquely enhances the rate
of L-selectin transient tether formation, and conversion
of tethers to rolling adhesions, providing further understanding of the shear threshold requirement for rolling
through L-selectin.
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