User:Immcarle75/sandbox

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01/30/18
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I'm planning on adding more about the structure of LFA-1 as well as the signal pathway that it is involved in. Specifically, I'd also like to look into the specific binding mechanisms between LFA-1 and ICAM. Finally, I will write about the other cytokines that LFA-1 interacts with. Potential sources:

Hintersteiner, M. et al. "Identification and X-Ray Co-Crystal Structure of a Small-Molecule Activator of Lfa-1-Icam-1 Binding." Angewandte Chemie-International Edition, vol. 53, no. 17, 2014, pp. 4322-4326, doi:10.1002/anie.201310240.

Ishibashi, M. et al. "Integrin Lfa-1 Regulates Cell Adhesion Via Transient Clutch Formation." Biochem Biophys Res Commun, vol. 464, no. 2, 2015, pp. 459-466, doi:10.1016/j.bbrc.2015.06.155.

Kang, S. et al. "Complex Structure of Engineered Modular Domains Defining Molecular Interaction between Icam-1 and Integrin Lfa-1." PLoS One, vol. 7, no. 8, 2012, doi:ARTN e44124 10.1371/journal.pone.0044124.

Oxford Dictionary of Biochemistry and Molecular Biology. Eds. Cammack, Richard, Teresa Atwood, Peter Campbell, Howard Parish, Anthony Smith, Frank Vella, and John Stirling. : Oxford University Press, 2006. Oxford Reference. 2008. Date Accessed 30 Jan. 2018 .

Reichardt, P. et al. "A Role for Lfa-1 in Delaying T-Lymphocyte Egress from Lymph Nodes." EMBO J, vol. 32, no. 6, 2013, pp. 829-843, doi:10.1038/emboj.2013.33.

2/6/18 Outline Expansion 1. Structure Section - Crystallized structure - Subunits - Overall composition - Integrin family (maybe into lead section) 2. LFA-1 & ICAM - Binding process - Discussion of relationship between two molecules - Final product/stage of interaction 3. Signal Pathway Outcomes - Cytokines - Adhesion of leukocytes to target cell - Interplay with monocytes, granulocytes, and cytotoxic t cells

LFA-1 is a heterodimeric glycoprotein with non-convalently linked subunits (Richardson). LFA-1 acts as an immune receptor on leucocytes (Hintersteiner). The a subunit of LFA-1 interacts with the first domain of the N subunit of ICAM. The first domain of the N subunit of ICAM has distinct epitopes for LFA-1 and human rhinovirus (Kang).

UPDATE 7th week: Revised Outline: 1. Structure Section: - Subunits - Composition 2. Discovery Section: - Discovery process 3. LFA-1 & Ligands - Description of ligands - Binding process - Signaling Pathway 4. Functions of LFA-1 - Cellular adhesion - interplay with monocytes, granulocytes, and cytotoxic t cells 5. LAD - Description of LAD molecularly - Effects of LAD physiologicaly

Draft 1: DISCOVERY Early discovery of cellular adhesion molecules involved the use of monoclonal antibodies to inhibit cellular adhesion processes. Once used, the specific antigen of the antibodies was identified as important in cellular recognition processes. These experiments produced the name “integrin” as a description of the proteins' integral parts in cellular adhesion processes and the transmembrane association between the extracellular matrix and the cytoskeleton. LFA-1 was was first discovered by Timothy Springer in mice (Schenkel).

STRUCTURE LFA-1 is a heterodimeric glycoprotein with non-convalently linked subunits (Richardson). LFA-1 is also known as alB2 integrin (Ishibashi). LFA-1 has two subunits: a and b. The alpha subunit was named aL in 1983. The alpha subunit is also known as CD11a and the common b unit-shared between all integrins-was named B2 (Schenkel).

LFA-1 & SUBUNITS As of 2007, LFA-1 has 6 known ligands: ICAM-1, ICAM-2, ICAM-3, ICAM-4, ICAM-5, and JAM-A (Schenkel).LFA-1 is activated by the activation of Rap1, an intracellular g-protein, by chemokines (Ishibashi).Once activated, Rap1 translocates to the plasma membrane. Rap 1 interacts with RapL, breaking the constraint between a and b subunits. This induces the intermediate extended conformation. This conformational change in the cytoskeleton exposes the binding b2 cytoplasmic binding domain for talin, a cytoskeleton protein. Talin is recruited by GTP-rap-1-rapl protein complex to form the integrin activation complex. (CPLAG!!) This further destabilizes the a and b subunits of LFA-1. The b1 subunit interacts with 17 helix and causes a downward movement, which causes the b1 like domain to become activated. The activation of the b1 like domain enables it to bind to its ligand, which allows for conformational changes that lead to a high-affinity conformation of LFA-1 (Schenkel). This is known as inside out signaling, which causes LFA-1 to shift from low affinity to high affinity by opening the ligand-binding site. IL-8 binds to LFA-1 to induce chemotaxis. LFA-1 in an inactive state has a low affinity and rests in a bent conformation (Li). LFA-1’s aL1 domain interacts with ICAM n-terminal D1 domain (Kang). ICAM-1 is upregulated as a response for inflammation (Kang).

FUNCTION: LFA-1 assists with emersion, the process of helping lymphocytes leave the bloodstream and enter tissue. LFA-1 assists with the slowing of neutrophils and the arrest of epithelial cells (Schenkel). LFA-1 mediates lymphocyte adhesion to the vessel wall and helps the lymphocytes enter the lymph node (Ishibashi). LFA-1 is involved in cytotoxic T-cell mediated killing of target cells and antibody-dependent killing of target cells by granulocytes and monocytes (CPLAG!) (Oxford Dict: LFA-1).

LAD: Leukocyte adhesion deficiency is an autoimmune deficiency caused by the absence of key adhesion surface proteins, including LFA-1. Patients with LAD have poorly functioning neutrophils (Schenkel). Infected leukocytes suffer from ineffective migration and phagocytosis. LAD 1 caused by lack of integrins that contain the b subunit, including LFA-1 (Oxford Dict: LAD). LAD is a genetic defect caused by autosomal recessive genes. Type 1 caused by low expression of CD11 and CD18. CD 18 found on chromosome 21 and CD 11 found on chromosome 16 (Kbari). LAD 1 is characterized by recurring bacterial infection, ineffective wound healing, pus formation, and granulocytosis (Anderson).

Draft 2:

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 was first discovered by Timothy Springer in mice in the 1980s (Schenkel).

STRUCTURE: LFA-1 is a heterodimeric glycoprotein with non-covalently linked subunits (Richardson). 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 also known as CD11a and the common b unit-shared between all integrins-was named B2 (Schenkel).

LFA-1 ACTIVATION & SUBUNITS: As of 2007, LFA-1 has 6 known ligands: ICAM-1, ICAM-2, ICAM-3, ICAM-4, ICAM-5, and JAM-A (Schenkel). 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). In an inactive state, LFA-1 rests in a bent conformation and has a low affinity for ICAM binding (Protein-protein). This bent conformation conceals the MIDAS (P-P). Chemokines stimulate the activation process of LFA-1 (pp). The activation process begins with the activation of Rap1, an intracellular g-protein (Schenkel). 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 (Schenkel). 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 (pp). This causes LFA-1 to undergo a conformational change to the fully extended conformation (pp). 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 (pp).

FUNCTION: As a cellular adhesion molecule, LFA-1 plays a key role in emersion, which is the process of helping lymphocytes leave the bloodstream and enter tissue. It also assists with the slowing of neutrophils and the arrest of epithelial cells (Schenkel). Additionally, LFA-1 is involved in the process of cytotoxic T cell mediated killing as well as antibody mediated killing by granulocytes and monocytes (Oxford Dict: LFA-1).

LAD: Leukocyte adhesion deficiency is an autoimmune deficiency caused by the absence of key adhesion surface proteins, including LFA-1. LAD is a genetic defect caused by autosomal recessive genes (Kbari). The deficiency causes ineffective migration and phagocytosis for impacted leukocytes (Oxford Dict: LAD). Patients with LAD also have poorly functioning neutrophils (Schenkel). LAD1, a subtype of LAD, is caused by a lack of integrins that contain the beta subunit, including LFA-1 (Oxford Dict: LAD). LAD1 is characterized by recurring bacterial infection, ineffective wound healing, pus formation, and granulocytosis (Anderson). LAD1 is caused by low expression of CD11 and CD18. CD18 is found on chromosome 21 and CD 11 is found on chromosome 16 (Kbari).