E-, P-, and L-Selectins

The inflammation response to tissue injury involves infiltration of damaged areas by leukocytes from the blood stream (1-4). Unregulated extravasation of leukocytes can result in inflammatory disorders such as reperfusion injuries, stroke, psoriasis, rheumatoid arthritis and respiratory diseases. An early step in the cascade of events leading to influx of leukocytes is the recognition of the tetrasaccharide sLex 1 (found on the terminus of leukocyte surface glycoproteins), by E, P and L selectins that are expressed by endothelial cells... 

Selectins are cell-adhesion molecules that mediate leukocyte recruitment in irmnune reactions and signal transduction. Selectins comprise three members termed E-, P-, and L-selectin. The CRD is located at the N-terminus, followed by an EGF-hke domain. There are various numbers of consensus repeat sequences following the EGF-like domain. P-selectin, L-selectin and E-selectin contain nine, six, and two repeats, respectively. A transmembrane segment and a cytoplasmic tail are located at the C-terminal. The key domains for target recognition and sugar binding are the N-terminal CRD and EGF-like domain. ... 

More recently, multivalent approaches [328,329,330] were reported. Based on molecular modeling approaches, non-sugar sLe mimetics [331,332,333] such as 107 (IC5o = 86, 6.1, and 30 jM for E-, P- and L-selectins respectively) [331] were created. A peptide mimicking the sialyl Lewis oligosaccharide has been identified [334], this concept is discussed in more detail the next chapter. 

Fig. 17.3 Domain structures of the E-, P-, and L-selectins (Paulson and Lasky 1992 copyright 1977 by W. H. Freeman and Company reproduced with kind permission from the editors).

Poppe et determined the conformation of the sLe tetrasaccharide in the free state and bound to E-, P-, and L-selectin-lg fusion proteins, from NMR measurements of interglycosidic coupling constants and nOe involving hydroxyl protons in slow chemical exchange at low temperatures." " From their data. 

G. Mannori, P. Crottet, O. Cecconi, K. Hanasaki, A. Aruffo, R.M. Nelson, A. Varki and M.P. Bevilacqua, Differential coloncancer cell adhesion to E-, P-, and L-selectin role of mucin-type glycoproteins. Cancer Res., 55 (1995) 4425-4431. 

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