Lymphotactin (Ltn) is the prototype and single member of the gamma or C class of chemokines. It is the only chemokine specific for T lymphocytes and NK cells, and is thought to be an important mediator of mucosal immune responses and some pathological autoimmune diseases. Ltn's therapeutic value has been demonstrated by its effect in accelerating antitumor responses in murine leukemias. Ltn is likely to have unique structural features due to its 20 residue C-terminal extension and its lack of one of the two disulfides conserved in other chemokines. The C class of chemokines is the only one for which no three-dimensional structure has been determined.
Specific Aim I will determine the structure of human Ltn by NMR spectroscopy and compare it to known structures of the CC, CXC and CX3C classes of chemokines. The extended C-terminus of Ltn has been implicated in its function, and this will be probed with a combination of mutagenesis and NMR spectroscopy in Specific Aim II. Chemokines bind to high affinity membrane-bound receptors and to glycosaminoglycan (GAG) components of extracellular matrix proteoglycans. The first receptor specific for Ltn has recently been identified. At present, chemokine:GAG interactions are not well understood, and no structural information exists for this binding reaction with Ltn. Experiments in the third Specific Aim will identify the glycosaminoglycan binding site of Ltn using NMR and mutagenesis, and solve the structure of a specific Ltn:heparin complex. The structural studies will identify regions of Ltn that are critical for function and will define a pathway for future rational drug design projects. Antagonists that prevent chemokine binding either to GAG or to the 7-transmembrane receptor may constitute new classes of immunotherapeutics. The complex biology of Ltn suggests that both positively acting analogs and antagonists will find clinical applications.
| Tuinstra, Robbyn L; Peterson, Francis C; Kutlesa, Snjezana et al. (2008) Interconversion between two unrelated protein folds in the lymphotactin native state. Proc Natl Acad Sci U S A 105:5057-62 |
| Kuloglu, E S; McCaslin, D R; Kitabwalla, M et al. (2001) Monomeric solution structure of the prototypical 'C' chemokine lymphotactin. Biochemistry 40:12486-96 |
