Selectins and their ligands

L-selectin ligands (addressins)

L-selectin receptors, also referred to as addressins, are localized predominantly on the surface of endothelial cells. The main representatives of this group of molecules include CD34, podocalyxin, endoglycan, and GlyCAM-1.

Structurally, most of them are transmembrane proteins. Their extracellular portion invariably contains a cysteine-rich region as well as a mucin domain of variable size. Endoglycan possesses an additional structural feature: a specific acidic region at the N-terminus.

The expression and activation of addressins have several important features:

• CD34 and podocalyxin are constitutively present on all endothelial cells, but in an inactive form. Their binding to L-selectin requires prior activation of endothelial cells by cytokines.
• In addition to the endothelium, the CD34 molecule is also expressed on stromal cells of lymphoid organs and on hematopoietic progenitor cells (including stem cells).
• The GlyCAM-1 molecule is unique in that it can exist in both classical membrane-bound and soluble forms. Its carbohydrate component within the mucin domain has a branched structure consisting of two branches.

Recognition mechanism and rolling process

The interaction of L-selectin with addressins is based on the recognition of the carbohydrate moiety of the ligand. Most frequently, this target is represented by sialylated determinants of Lewis blood group antigens, known as sLe^x (or CD15). Structurally, this complex represents the sequence Sia α2→3 Gal β1→4Fuc α1→GlcNAc.

To strengthen the bond, sulfation of this determinant is required—a process involving the attachment of a negatively charged SO3- group to a galactose or N-acetylglucosamine residue. However, even after such modification, L-selectin forms an exclusively weak bond with addressins.

An additional instability is introduced into the cellular contact by shedding (shedding), a process in which L-selectin molecules are rather easily cleaved and washed off the surface. Consequently, the bond between the leukocyte and the endothelial cell remains unstable. The physiological manifestation of such weak interaction is leukocyte rolling (rolling) along the blood vessel wall. This exact phenomenon marks the beginning of the complex process of leukocyte emigration from the vascular bed into tissues.

Interaction with E- and P-selectins

Unlike L-selectin, E- and P-selectins are expressed exclusively on endothelial cells (induced by proinflammatory cytokines) and are completely absent on the surface of leukocytes themselves. To adhere to the activated endothelium, leukocytes utilize a set of specific E- and P-selectin receptors:

1. PSGL-1 (P-selectin glycoprotein ligand-1, also designated as CD162).
2. CLA (Cutaneous lymphocyte antigen), which is structurally a fucosylated derivative of the PSGL-1 molecule.
3. Various mucins containing the sLe^x carbohydrate determinant (e.g., CD66 and CD24 molecules).
4. Certain members of the integrin family (specifically, the α4β7 complex).

Characteristics of PSGL-1 and CLA receptors

Structurally, the PSGL-1 molecule is a complex sialomucin containing O- and N-glycosylation sites (attached via tyrosine amino acid residues). This receptor can be found on the surface of monocytes, neutrophils, and the vast majority of lymphocytes. A crucial prerequisite for PSGL-1 binding to selectins is the attachment of a sulfate group to the tyrosine residue located in the N-terminal part of the protein.

In addition to mediating physical contact, PSGL-1 actively participates in intracellular signaling. Its long cytoplasmic domain is directly coupled to Syk tyrosine kinase, enabling the unobstructed transmission of activation signals from the surface into the cell interior.

A specialized modification of PSGL-1 is the cutaneous lymphocyte antigen, CLA. It is formed on certain T-cell pools through the direct involvement of a specific enzyme, α1,3-fucosyltransferase VII. The primary function of CLA is to direct the targeted migration of T lymphocytes into the epidermis. This is achieved through the high affinity of the CLA molecule for E-selectin expressed on the vascular endothelium of the skin.

Subsequent stages of cell adhesion are mediated by integrins—the most crucial and multifunctional molecules capable of connecting the extracellular and intracellular environments of the cell by transmitting signals in both directions.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• The mechanism of intracellular signaling involving Syk tyrosine kinase
• Structure and functions of the sLe^x (CD15) determinant
• The role of the enzyme α1,3-fucosyltransferase VII in the immune system
• Features of CD34 expression on hematopoietic stem cells
• Integrins as adhesion molecules: structure and bidirectional signaling

Other topics in the "Innate Immunity" section

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