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Lymphocyte function-associated antigen 1

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Lymphocyte function-associated antigen 1 (LFA-1) is a cellular adhesion molecule 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 stimulate signaling pathways that influence T cell differentiation.[4] LFA-1 belongs to the integrin superfamily of adhesion molecules.[1]

Structure

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 also known as CD11a and the common b unit—shared between all integrins—is referred to as B2.[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]

Activation

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]

Discovery

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 (LAD)

Leukocyte adhesion deficiency is an autoimmune deficiency 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, ineffective wound healing, 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]

See also

References

  1. ^ a b M., Lackie, J. (2010). A dictionary of biomedicine (1st ed ed.). Oxford: Oxford University Press. ISBN 9780191727948. OCLC 663104793. {{cite book}}: |edition= has extra text (help)CS1 maint: multiple names: authors list (link)
  2. ^ a b c d e f g h i j k l m n Adhesion molecules : function and inhibition. Ley, Klaus, 1957-. Basel: Birkhauser. 2007. ISBN 9783764379759. OCLC 261225084.{{cite book}}: CS1 maint: others (link)
  3. ^ a b c d Oxford dictionary of biochemistry and molecular biology. Cammack, Richard, Ph. D. (Rev. ed ed.). Oxford: Oxford University Press. 2006. ISBN 9780191727641. OCLC 743217704. {{cite book}}: |edition= has extra text (help)CS1 maint: others (link)
  4. ^ Verma NK, Kelleher D (August 2017). "Not Just an Adhesion Molecule: LFA-1 Contact Tunes the T Lymphocyte Program". Journal of Immunology. 199 (4): 1213–1221. doi:10.4049/jimmunol.1700495. PMID 28784685.
  5. ^ a b c d e f g Protein-protein interactions in drug discovery. Dömling, Alexander. Weinheim: Wiley-VCH. 2013. ISBN 9783527648238. OCLC 828743731.{{cite book}}: CS1 maint: others (link)
  6. ^ a b c Akbari, H.; Zadeh, M. M. (January 2001). "Leukocyte adhesion deficiency". Indian Journal of Pediatrics. 68 (1): 77–79. ISSN 0019-5456. PMID 11237241.
  7. ^ Anderson, D. C.; Springer, T. A. (1987). "Leukocyte adhesion deficiency: an inherited defect in the Mac-1, LFA-1, and p150,95 glycoproteins". Annual Review of Medicine. 38: 175–194. doi:10.1146/annurev.me.38.020187.001135. ISSN 0066-4219. PMID 3555290.

Further reading

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