Lymphocyte function-associated antigen 1 (LFA-1) is an

integrin Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle ...

found on

lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...

s and other leukocytes. LFA-1 plays a key role in emigration, which is the process by which leukocytes leave the bloodstream to enter the tissues. LFA-1 also mediates firm arrest of leukocytes. Additionally, LFA-1 is involved in the process of cytotoxic T cell mediated killing as well as antibody mediated killing by granulocytes and monocytes. As of 2007, LFA-1 has 6 known ligands:

ICAM-1 ICAM-1 ( Intercellular Adhesion Molecule 1) also known as CD54 (Cluster of Differentiation 54) is a protein that in humans is encoded by the ''ICAM1'' gene. This gene encodes a cell surface glycoprotein which is typically expressed on endothelial ...

, ICAM-2, ICAM-3, ICAM-4, ICAM-5, and JAM-A. LFA-1/ICAM-1 interactions have recently been shown to stimulate signaling pathways that influence T cell differentiation. LFA-1 belongs to the

superfamily of adhesion molecules.

Structure

LFA-1 is a heterodimeric glycoprotein with non-covalently linked subunits. LFA-1 has two subunits designated as the alpha subunit and beta subunit. The alpha subunit was named aL in 1983. The alpha subunit is designated CD11a; and the beta subunit, unique to leukocytes, is beta-2 or CD18. The ICAM binding site is on the alpha subunit. The general binding region of the alpha subunit is the I-domain. Due to the presence of a divalent cation site in the I-domain, the specific binding site is often referred to as the metal-ion dependent adhesion site (MIDAS).

Activation

In an inactive state, LFA-1 rests in a bent conformation and has a low affinity for ICAM binding. This bent conformation conceals the MIDAS.

Chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additio ...

s stimulate the activation process of LFA-1. The activation process begins with the activation of

Rap1 Rap1 (Ras-proximate-1 or Ras-related protein 1) is a small GTPase, which are small cytosolic proteins that act like cellular switches and are vital for effective signal transduction. There are two isoforms of the Rap1 protein, each encoded by ...

, an intracellular g-protein. Rap1 assists in breaking the constraint between the alpha and beta subunits of LFA-1. This induces an intermediate extended conformation. The conformational change stimulates a recruitment of proteins to form an activation complex. The activation complex further destabilizes the alpha and beta subunits. Chemokines also stimulate an I-like domain on the beta subunit, which causes the MIDAS site on the beta subunit to bind to glutamate on the I domain of the alpha subunit. This binding process causes the beta subunit to pull down the alpha 7 helix of the I domain, exposing and opening up the MIDAS site on the alpha subunit for binding. This causes LFA-1 to undergo a conformational change to the fully extended conformation. The process of activating LFA-1 is known as inside out signaling, which causes LFA-1 to shift from low affinity to high affinity by opening the ligand-binding site.

Discovery

Early discovery of cellular adhesion molecules involved the use of monoclonal antibodies to inhibit cellular adhesion processes. The antigen that bound to the monoclonal antibodies was identified as an important molecule in cellular recognition processes. These experiments yielded the protein name “integrin” as a description of the proteins' integral role in cellular adhesion processes and the transmembrane association between the extracellular matrix and the cytoskeleton. LFA-1, a leukocyte integrin, was first discovered by Timothy Springer in mice in the 1980s.

Leukocyte Adhesion Deficiency (LAD)

Leukocyte adhesion deficiency Leukocyte adhesion deficiency (LAD) is a rare autosomal recessive disorder characterized by immunodeficiency resulting in recurrent infections. LAD is currently divided into three subtypes: LAD1, LAD2, and the recently described LAD3, also kno ...

is an immunodeficiency caused by the absence of key adhesion surface proteins, including LFA-1. LAD is a genetic defect caused by autosomal recessive genes. The deficiency causes ineffective migration and phagocytosis for impacted leukocytes. Patients with LAD also have poorly functioning neutrophils. LAD1, a subtype of LAD, is caused by a lack of integrins that contain the beta subunit, including LFA-1. LAD1 is characterized by recurring bacterial infection, delayed (>30 days) separation of umbilical cord, ineffective wound healing and pus formation, and granulocytosis. LAD1 is caused by low expression of CD11 and CD18. CD18 is found on chromosome 21 and CD11 is found on chromosome 16.

References

External links

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ITGAL ITGB2
Info with links in th
Cell Migration Gateway
{{Integrins Immunology Integrins