Lymphocyte function-associated (LFA) molecules and intercellular adhesion molecules (ICAMs) are important both in antigen-specific interactions in immune responses and in interactions with endothelial cells during leukocyte localization in inflammation. LFA-1 is an alpha/beta heterodimer and a member of the integrin family. It binds to 3 ICAMs, (ICAM-1, ICAM-2, and ICAM-3) that are members of the Ig superfamily (IgSF) and are closely related (35-55%) to one another. ICAM-4 and ICAM-5 are further homologues that bind more weakly to LFA-1. The physiologic importance of these molecules is demonstrated by effect of deficiency of LFA-1 in an inherited disease, LAD; effect of ICAM-1 deficiency in mice; and effect of mAb to these molecules in inhibiting antigen-specific T lymphocyte responses, graft rejection, and animal models of disease. Studies of the function of these molecules in health and disease, the regulation of adhesiveness through them, and the structure of their interaction sites is of great importance, and may lead to the development of novel anti- inflammatory agents. We will determine the structure of domains 3, 4, and 5 in ICAMs, reconstruct the architecture of dimeric ICAM-1 on the cell surface, and determine the function of dimerization in binding to LFA-1. The hypothesis that the LFA-1 I domain exists in high and low affinity states will be examined with mutations that stabilize these states, determining the binding sites and inhibitory mechanisms of antibodies, and determining the structure of the LFA-1 I domain complexed with 1 or 2 domain fragments of ICAM-1. A low-resolution structure of LFA-1 will include information on domain associations and their alteration in activation. The crystal structure will be determined for LFA-1 or its fragments.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA031798-22
Application #
6512410
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Gallahan, Daniel L
Project Start
1981-07-01
Project End
2004-02-29
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
22
Fiscal Year
2002
Total Cost
$550,993
Indirect Cost
Name
Immune Disease Institute, Inc.
Department
Type
DUNS #
115524410
City
Boston
State
MA
Country
United States
Zip Code
02115
Feng, Juan; Dong, Xianchi; Pinello, Jennifer et al. (2018) Fusion surface structure, function, and dynamics of gamete fusogen HAP2. Elife 7:
Clutton, Genevieve Tyndale; Jones, R Brad (2018) Diverse Impacts of HIV Latency-Reversing Agents on CD8+ T-Cell Function: Implications for HIV Cure. Front Immunol 9:1452
Sen, Mehmet; Koksal, Adem C; Yuki, Koichi et al. (2018) Ligand- and cation-induced structural alterations of the leukocyte integrin LFA-1. J Biol Chem 293:6565-6577
Moore, Travis I; Aaron, Jesse; Chew, Teng-Leong et al. (2018) Measuring Integrin Conformational Change on the Cell Surface with Super-Resolution Microscopy. Cell Rep 22:1903-1912
Swaminathan, Vinay; Kalappurakkal, Joseph Mathew; Mehta, Shalin B et al. (2017) Actin retrograde flow actively aligns and orients ligand-engaged integrins in focal adhesions. Proc Natl Acad Sci U S A 114:10648-10653
Nordenfelt, Pontus; Moore, Travis I; Mehta, Shalin B et al. (2017) Direction of actin flow dictates integrin LFA-1 orientation during leukocyte migration. Nat Commun 8:2047
Nordenfelt, Pontus; Elliott, Hunter L; Springer, Timothy A (2016) Coordinated integrin activation by actin-dependent force during T-cell migration. Nat Commun 7:13119
Sen, Mehmet; Springer, Timothy A (2016) Leukocyte integrin ?L?2 headpiece structures: The ?I domain, the pocket for the internal ligand, and concerted movements of its loops. Proc Natl Acad Sci U S A 113:2940-5
Martinelli, Roberta; Kamei, Masataka; Sage, Peter T et al. (2013) Release of cellular tension signals self-restorative ventral lamellipodia to heal barrier micro-wounds. J Cell Biol 201:449-65
Schurpf, Thomas; Springer, Timothy A (2011) Regulation of integrin affinity on cell surfaces. EMBO J 30:4712-27

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