Structure and Function of the T-cell Receptor Zeta Chain Cytoplasmic Domain

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Structure and Function of the T-cell Receptor Zeta Chain Cytoplasmic DomainT cells are activated upon encounter with another cell that carries on its surface a peptide antigen bound to an MHC protein, as part of the process by which foreign material in the body is recognized and cleared by the immune system. The interaction involves specific recognition of the MHC-peptide complexes by clonotypic T-cell receptor (TCR) subunits, as well as antigen-independent interactions between adhesion molecules and other cell surface receptors from the T cell and the antigen presenting cell. Clustering of TCR complexes at the T-cell surface using antibodies or multivalent antigens can induce T cell processes characteristic of interaction with an antigen-presenting cell, suggesting that clustering or aggregation of TCR components isimportant for initiation of T-cell activation. Cytoplasmic domains of the TCR gamma, delta, epsilon, and particularly zeta subunits are responsible for transmitting extracellular binding signals into the T cell. Unlike other cell surface receptor systems activated by oligomerization, TCR cytoplasmic domains do not appear to carry intrinsic or associated enzymatic activities. Membrane-bound and cytoplasmic kinases interact with TCR cytoplasmic domains upon antigen engagement, triggering cytoplasmic signaling cascades. Despite intensive study, the mechanism by which clustering of T-cell surface receptors can leads to cytoplasmic signaling is not clear and is a major outstanding problem in the field. In the proposed research, the structure and function of the TCR zeta chain cytoplasmic domain will be investigated. Specifically, a newly discovered lipid-binding activity will be characterized. Lipid binding induces a structural alteration in the TCR zeta chain cytoplasmic domain, and the conforynational change controls accessibility to src- family kinases in vitro. Possible roles of this lipid binding activity and conformational change in the T-cell activation pathway will be investigated. The specific objectives or the proposed research are to determine the requirements for inducing the lipid-dependent conforrnational change, to produce a detailed structural description of the lipid-bound structure, to investigate the confon-national change of cytoplasmic domain in the context of the full-length zeta subunit protein, and to evaluate the importance of the conformational change in signaling processes in vivo. These objectives will be pursued through a variety of spectroscopic studies of purified receptor cytoplasmic domains in complex with various detergents and lipids, and biochemical assays of signaling processes in vitro and in vivo.