T cells are key players in the defense against infectious disease and cancer. Although much is known about T-cell development, selection, signaling, activation and apoptosis, many of the crucial events are not yet understood at a mechanistic level. The goal of the research proposed here is to provide new molecular and structural insights into signaling mechanisms as relevant for T-cell function. The proposed research is a continuation of a successful project that has lead in the past to a number of important structural and functional insights into the structural organization of the TCR/CD3 complex, intracellular and extracellular interactions of T-cell surface receptors and intracellular signaling mechanisms. The research proposed here has the goal to define protein interactions between invariant and clonotypic components of the TCR complex, as well as between TCR components and ligands outside and inside the plasma membrane. This will provide new insights into the mechanisms of TCR signal transduction. In addition we propose to study intracellular interactions crucial for T-cell signaling. It appears that some of the interactions within the components of the TCR complex are weak and transient. Thus, the planned research also includes the development and application of sensitive techniques that can identify and characterize such weak interactions with spatial resolution. The current proposal will pursue the following specific aims: 1. Characterize structures and interactions of invariant and clonotypic components of the T-cell receptor complex 2. Study structure and interactions of the cytosolic adaptor protein Nek and its potential function as a cellular switch in T cells. 3. Investigate the mode of interactions between the phosphatase calcineurin between nuclear factor of activated T-cells and mechanisms for inhibition of T-cell activation ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI037581-11
Application #
7095474
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Rathbun, Gary
Project Start
1996-07-15
Project End
2011-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
11
Fiscal Year
2006
Total Cost
$321,625
Indirect Cost
Name
Harvard University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Brazin, Kristine N; Mallis, Robert J; Boeszoermenyi, Andras et al. (2018) The T Cell Antigen Receptor ? Transmembrane Domain Coordinates Triggering through Regulation of Bilayer Immersion and CD3 Subunit Associations. Immunity 49:829-841.e6
Mallis, Robert J; Arthanari, Haribabu; Lang, Matthew J et al. (2018) NMR-directed design of pre-TCR? and pMHC molecules implies a distinct geometry for pre-TCR relative to ??TCR recognition of pMHC. J Biol Chem 293:754-766
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Nasr, Mahmoud L; Baptista, Diego; Strauss, Mike et al. (2017) Covalently circularized nanodiscs for studying membrane proteins and viral entry. Nat Methods 14:49-52
Coote, Paul; Anklin, Clemens; Massefski, Walter et al. (2017) Rapid convergence of optimal control in NMR using numerically-constructed toggling frames. J Magn Reson 281:94-103
Das, Dibyendu Kumar; Mallis, Robert J; Duke-Cohan, Jonathan S et al. (2016) Pre-T Cell Receptors (Pre-TCRs) Leverage V? Complementarity Determining Regions (CDRs) and Hydrophobic Patch in Mechanosensing Thymic Self-ligands. J Biol Chem 291:25292-25305

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