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Lymphocyte function-associated antigen 1

LFA-1 is a heterodimeric glycoprotein with non-covalently linked subunits.^[3] LFA-1 has two subunits designated as the alpha subunit and beta subunit.^[2] The alpha subunit was named aL in 1983.^[2] The alpha subunit is designated CD11a; and the beta subunit, unique to leukocytes, is beta-2 or CD18.^[2] The ICAM binding site is on the alpha subunit.^[5] 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).^[5]

In an inactive state, LFA-1 rests in a bent conformation and has a low affinity for ICAM binding.^[5] This bent conformation conceals the MIDAS. Chemokines stimulate the activation process of LFA-1.^[5] The activation process begins with the activation of Rap1, an intracellular g-protein.^[2] Rap1 assists in breaking the constraint between the alpha and beta subunits of LFA-1.^[2] This induces an intermediate extended conformation.^[2] The conformational change stimulates a recruitment of proteins to form an activation complex. The activation complex further destabilizes the alpha and beta subunits.^[2] 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.^[5] 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.^[5] 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.^[5]

Early discovery of cellular adhesion molecules involved the use of monoclonal antibodies to inhibit cellular adhesion processes.^[2] The antigen that bound to the monoclonal antibodies was identified as an important molecule in cellular recognition processes.^[2] 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.^[2] LFA-1, a leukocyte integrin, was first discovered by Timothy Springer in mice in the 1980s.^[2]

Leukocyte adhesion deficiency is an immunodeficiency caused by the absence of key adhesion surface proteins, including LFA-1.^[6] LAD is a genetic defect caused by autosomal recessive genes.^[6] The deficiency causes ineffective migration and phagocytosis for impacted leukocytes.^[3] Patients with LAD also have poorly functioning neutrophils.^[2] LAD1, a subtype of LAD, is caused by a lack of integrins that contain the beta subunit, including LFA-1.^[3] LAD1 is characterized by recurring bacterial infection, delayed (>30 days) separation of umbilical cord, ineffective wound healing and pus formation, and granulocytosis.^[7] LAD1 is caused by low expression of CD11 and CD18. CD18 is found on chromosome 21 and CD11 is found on chromosome 16.^[6]

• Leukocyte adhesion deficiency
• Lifitegrast, a drug that blocks LFA-1 from binding to ICAM-1

• LFA-1 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• ITGAL ITGB2 Info with links in the Cell Migration Gateway