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Fig 10. LFA-1/Mac-1 binding regions of ICAM-1 and ICAM-2. The crystal structures of ICAM-1 domains 1-5 (D1-D5) (A) and ICAM-2 domain 1 (D1) (C) are shown. (A) This ICAM-1 D1-D5 model was constructed by linking the known D1-D2 structure and D3-D5 structure reported here at the pivot residue Val-186. The key LFA-1 binding site Glu-34 of D1 and the Mac-1 binding sites Asp-229 and Glu-254 of D3 (all shown in ball-and-stick representation) point upward, available for ligand binding from the opposing cell above. Note that the Glu-34 is on a relatively flat surface, whereas the Asp-229 is on a protruded loop. All seven identified glycans are shown in ball-and-stick representation (prepared with RIBBONS [Carson, 1995]). A is reprinted from Molecular Cell, Yang et al, 2004. Copyright (2004), with permission from Elsevier. (C) The backbone of ICAM-2 is shown in grey as a ribbon diagram with E-strands lettered. Disulfide bonds are shown in grey.
Side chains of individual residues tested by mutagenesis are shown as ball and stick. The carbons and bonds of these side chains are color-coded according to the percentage of wildtype binding to LFA-1 after mutagenesis, red, <35%; yellow-orange, 35-70%; green, >70%; magenta, <35% with a possible effect on domain structure. Side chain oxygen and nitrogen atoms are yellow and blue, respectively. C is reprinted from Proceedings of the National Academy of Sciences, Casasnovas et al, 1999. Copyright (1999), with permission from National Academy of Sciences, U.S.A. B and D are the ICAM-1 and ICAM-2 schematic models on cell membrane. The tripod-like array of N-glycans in ICAM-2 domain 2 are shown in blue (D). Modified from Li Tian’s thesis: ICAM-5 (Telencephalin) – a Novel Cell Adhesion Molecule, 2001.
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Fig 11. ICAM-1 binding to LFA-1 leads to cytoskeletal reorganization. (A) ICAM-1 monomers dimerize to the O-form (Yang et al, 2004). ERM proteins and D-actinin (1 and/or 4) bind to the ICAM-1 cytoplasmic tail. (B) ICAM-1 binding to LFA-1 results in conformational changes in both proteins, and this leads to W-form clustering. Ezrin and moesin detach from the ICAM-1 cytoplasmic domain. D-Actinin can still bind, and then cortactin joins the ICAM-1 cluster. The Src-family kinases phosphorylate cortactin. In this way, cytoskeletal reorganization may be the result of ICAM-1 clustering. PMN, polymorphonuclear neutrophil. Modified from Progress in Inflammation Research, Adhesion Molecules: Function and Inhibition, Auerbach et al, 2007.
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Fig 12. A model of ȕ2 integrin/ICAM-1-mediated signal transduction. ICAM-1 multimers form after binding to E2 integrins (LFA-1, Mac-1). Src-family kinases phosphorylate ICAM-1 cytoplasmic domain. Adaptor proteins, such as Grb2, SOS and Shc help ICAM-1 in signal transduction. The MAPK pathway is activated, and ERKs also become activated. This leads to transcription factor activation, and the results are cell proliferation, cytokine production and increased cell surface receptor expression. Modified from Hubbard and Rothlein, 2000.
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Fig 13. ICAM-mediated signalling models and the involvement of ICAM-3. In A, LFA-1 on T cells binds with low affinity to ICAM-3 on the target cell (1). The target cell expresses also ICAM-1 and ICAM-2. LFA-1 binding to ICAM-3 promotes LFA-1 clustering (2). Anti-CD3 triggering or antigen recognition leads to generation of intracellular signals, increased LFA-1 binding affinity for ICAM-1 (3). LFA-1 binds to ICAM-1 to form a stable interaction (4). The LFA-1/ICAM-1 interaction also leads to signal transduction with the result being T cell proliferation, cytotoxicity and gene expression.
Modified from Bleijs et al, 2000. In B, DC-SIGN on DC and ICAM-3 on T cell bind to each other (1). Low-avidity interactions can form between DCs and T cells. LFA-1/ICAM-1 interaction helps in antigen-independent DC-T cell clustering (2). T cell receptor (TCR) ligation (3) leads to signal transduction, and high-avidity CD2/LFA-3 and LFA-1/ICAM-1 interactions result in immunological synapse stabilization. The LFA-1/ICAM-1 interaction is seen in the outer ring. CD2/LFA-3 and TCR/MHC/peptide are found in the center of the immunological synapse (4). Modified from Geijtenbeek et al, 2000.
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