Structure and evolution of potassium channels and immunoglobulin super-family genes
Research in our laboratory has been directed toward the application of molecular and computer-based tools to study the organization, molecular evolution and expression of several gene families of immunological interest, which have included immunoglobulins as well as T-cell receptors. Recent work has focused on a collaborative study of an extensive family of voltage-gated potassium (K+) channels known to be important in T-lymphocyte function. In addition to their fundamental interest for understanding cell signalling mechanisms, their intriguing associations with a variety of autoimmune states have marked them as potential targets for drug-based therapy of this important group of diseases. A family of scorpion toxins of known structure, which are high-affinity blockers of this channel, have been used as molecular "calipers" to define the structure of the outer mouth of the channel; site-directed mutagenesis combined with molecular modelling have already identified a number of interactive pairs of residues in the channel and in the toxin, as well as intermolecular distances. We are also interested in developing a better understanding of the evolutionary relationships between ion channels (including potassium, sodium and calcium channels, as well as cyclic nucleotide-binding channels), and defining the evolutionary events which have resulted in their present diversity and complex gene organization. Various phylogeny reconstruction methods have been applied to amino acid and nucleotide sequence alignments of this superfamily of membrane proteins.
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Negulescu, D., Leong, L. E.-C., Chandy, K. G., Semler, B. L., Gutman, G.A. (1998) Translation initiation of a cardiac voltage-gated potassium channel by internal ribosome entry. J. Biol. Chem. 237:20109-20113
Chandy, K. G., Strong, M., Aiyar, J., Spencer, R., Gutman, G. A. (1997) Structural and biochemical features of the type-n K channel in T-cells: A prerequisite to guided drug design. Cell. Physiol. Biochem. 7:135-147.
Wymore, R.S., Negulescu, D., Kinoshita, K., Kalman, K., Aiyar, J., Gutman, G.A., and Chandy, K.G. (1996) Characterization of the transcription unit of mouse Kv1.4, a voltage-gated potassium channel gene. J. Biol. Chem. 271:15629-34.
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