出典(authority):フリー百科事典『ウィキペディア(Wikipedia)』「2019/04/14 01:40:57」(JST)
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]
Membrane proteins: cell adhesion molecules | |||||||||||||
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Calcium-independent |
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Calcium-dependent |
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Other |
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Integrins | |||||||||||||
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Alpha |
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Beta |
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Dimers |
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see also cell surface receptor deficiencies |
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リンク元 | 「LFA-1」「リンパ球機能関連抗原1」 |
関連記事 | 「associate」「function」「associated」「lymphocyte」 |
first aid step1 2006 p.190
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