Lymphocyte function-associated antigen 1 (LFA-1) is an integrin found on lymphocytes and other leukocytes. [1] 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. [2] Additionally, LFA-1 is involved in the process of cytotoxic T cell mediated killing as well as antibody mediated killing by granulocytes and monocytes. [3] As of 2007, LFA-1 has 6 known ligands: ICAM-1, ICAM-2, ICAM-3, ICAM-4, ICAM-5, and JAM-A. [2] LFA-1/ICAM-1 interactions have recently been shown to stimulate signaling pathways that influence T cell differentiation. [4] LFA-1 belongs to the integrin superfamily of adhesion molecules. [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]
Lymphocyte function-associated antigen 1 (LFA-1) is an integrin found on lymphocytes and other leukocytes. [1] 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. [2] Additionally, LFA-1 is involved in the process of cytotoxic T cell mediated killing as well as antibody mediated killing by granulocytes and monocytes. [3] As of 2007, LFA-1 has 6 known ligands: ICAM-1, ICAM-2, ICAM-3, ICAM-4, ICAM-5, and JAM-A. [2] LFA-1/ICAM-1 interactions have recently been shown to stimulate signaling pathways that influence T cell differentiation. [4] LFA-1 belongs to the integrin superfamily of adhesion molecules. [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]