Adhesion of cells to other cells or to the cellular matrix is crucial in many biological processes. Leukocyte, in particular, is vital for the immune system. There are several adhesion molecule families, of which integrins are the most versatile. Because of their large size and complexity, there is little structural information available, compared to other adhesion molecule families. This proposal aims to determine the crystal structures of one integrin molecule (beta2 integrins or an """"""""easy"""""""" integrins), or dissect one integrin by determining structures of its subunits and fragments. As a continuation from the previous grant period, we will also determine the structure of the whole extracellular portion of ICAM-1 (or ICAM-3 or ICAM-5) as well as a complex of binding domain from beta2- integrin with ligand such as fragment of ICAM-1, ICAM-2 or ICAM-3. We would like to eventually help unravel the mechanism of """"""""inside-out"""""""" and """"""""outside-in"""""""" signaling associated with these adhesion molecules from the structural point of view. This is extremely important for understanding how the adhesion is regulated in response to stimuli in various tissues. Finally we will also carry out structure analyses of the beta-propeller domain (the critical ligand-binding domain in integrin) from the extracellular portion of other cell surface proteins, such as nidogen, and even some bacterial proteins that contain beta-propellers very similar to those found in integrins. We would like to explore the evolutionary trial of the beta-propeller domain as an important module used in protein-protein interactions in various cell recognition processes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL048675-09
Application #
6492329
Study Section
Project Start
2001-08-31
Project End
2002-08-31
Budget Start
Budget End
Support Year
9
Fiscal Year
2001
Total Cost
$310,488
Indirect Cost
Name
Immune Disease Institute, Inc.
Department
Type
DUNS #
115524410
City
Boston
State
MA
Country
United States
Zip Code
02115
Finci, L; Zhang, Y; Meijers, R et al. (2015) Signaling mechanism of the netrin-1 receptor DCC in axon guidance. Prog Biophys Mol Biol 118:153-60
Jiang, Jian-kang; McCoy, Joshua G; Shen, Min et al. (2014) A novel class of ion displacement ligands as antagonists of the ?IIb?3 receptor that limit conformational reorganization of the receptor. Bioorg Med Chem Lett 24:1148-53
Liu, Ying; Zhang, Yan; Wang, Jia-Huai (2014) Crystal structure of human Ankyrin G death domain. Proteins 82:3476-82
Finci, Lorenzo I; Krüger, Nina; Sun, Xiaqin et al. (2014) The crystal structure of netrin-1 in complex with DCC reveals the bifunctionality of netrin-1 as a guidance cue. Neuron 83:839-849
Chen, Qiang; Sun, Xiaqin; Zhou, Xiao-hong et al. (2013) N-terminal horseshoe conformation of DCC is functionally required for axon guidance and might be shared by other neural receptors. J Cell Sci 126:186-95
Wang, Jia-Huai (2013) The sequence signature of an Ig-fold. Protein Cell 4:569-72
Xu, Amy J; Springer, Timothy A (2013) Mechanisms by which von Willebrand disease mutations destabilize the A2 domain. J Biol Chem 288:6317-24
Xu, Amy J; Springer, Timothy A (2012) Calcium stabilizes the von Willebrand factor A2 domain by promoting refolding. Proc Natl Acad Sci U S A 109:3742-7
Wang, Jia-huai; Reinherz, Ellis L (2012) The structural basis of ?? T-lineage immune recognition: TCR docking topologies, mechanotransduction, and co-receptor function. Immunol Rev 250:102-19
Yu, Yamei; Zhu, Jianghai; Mi, Li-Zhi et al. (2012) Structural specializations of ?(4)?(7), an integrin that mediates rolling adhesion. J Cell Biol 196:131-46

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