PROBING CELLULAR ADHESION AT THE SINGLE-MOLECULE LEVEL - Life at the Nanoscale: Atomic Force Microscopy of Live Cells - page 245

membrane tether at physiological low velocities, optimizing rolling. In turn,
integrin

1 binding to ibronectin would last longer at the forces exerted
by the actomyosin cytoskeleton during cell migration, unbinding faster when
force is released. Indeed, Forero and coworkers have recently shown that
the uncoiling mechanism of

A B

5

E. coli type I imbrae is optimized for catch bond

behavior.

87

11.4 LEUKOCYTE ADHESION TO THE VASCULAR
ENDOTHELIUM

Leukocytes circulating in the blood vessels need to exit the bloodstream to
enter speciic tissues or areas of inlammation.

This inely tuned process is
mediated by the interactions between leukocyte adhesion molecules, typically
selectins, selectin ligands and integrins, and their adhesive partners expressed
on the inner surface of the blood vessel wall. If this adhesive process is not
under proper control, it could lead to severe diseases such as autoimmune
diseases, asthma and atherosclerosis. 88 We will discuss later how the AFM
approaches may provide better understanding of the molecular mechanism
of leukocyte adhesion.

3

11.4.1 Selecns

The selectins are calcium-dependent, type I transmembrane glycoproteins
that bind to sialylated carbohydrate moieties present on target proteins ( Fig.
11.1 ). 89 Consisting of three members, P-selectin, E-selectin and L-selectin,
selectins initiate leukocyte rolling on vascular endothelial cells during
inlammatory responses. Structurally, the three selectins are very similar to
each other and are composed of ive types of domains ( Fig. 11.1 ) , starting
from the N-terminal: a calcium-dependent lectin domain, an epidermal
growth factor-like domain, a series of short-consensus-repeat domains, a
transmembrane domain and a cytoplasmic tail ( Fig. 11.1 ). The ligands for
selectins are various glycoproteins, including PSGL-1, E-selectin ligand-
1, glycosylation-dependent CAM-1 and CD34. Each of these ligands has a
conjugated carbohydrate containing four sugar groups called sialyl Lewis X
(sLeX), which forms the major binding site for all selectins. This interaction can
be further strengthened by some amino acid residues within the ligands. 90
Selectin-ligand interactions have been studied using AFM and other single-
molecular approaches ( Table 11.1 ) . One of the earlier studies conducted by
Fritz et al. , using a PSGL-1/IgG functionalized tip interacting with P-selectin-