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January 2010 - March 2011

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University of Minnesota Twin Cities
College of Pharmacy
Department of Experimental and Clinical Pharmacology

PI: Ramaiah Muthyala

Protein-Protein Interactions: Rare Neurological Diseases

The 14-3-3 proteins are a family of conserved regulatory molecules expressed in eukaryotic cells. A striking feature of the 14-3-3 proteins is their ability to bind a multitude of functionally diverse signaling proteins, including kinases, phosphatases, and trans-membrane receptors, and to participate in the regulation of diverse biological processes such as neuronal development, cell growth control, and viral and bacterial pathogenesis. 14-3-3 is a family of highly homologous proteins, encoded by separate genes and existing mainly as dimers. The sheer number of binding partners for 14-3-3 allows the prediction of some properties of the interaction, such that these proteins share common-binding determinants that mediates their contact with 14-3-3. One such determinant is a specifically phosphorylated residue in ligands. It is well known that phosphorylated serene in the ligand serves as a recognition signal for protein-protein interactions.

14-3-3 proteins have been implicated in a variety of pathological processes. The abundance of 14-3-3 proteins is in various organs, in particular brain tissue, points to its critical role in neurological diseases. It is found in the neurofibrilalary tangles seen in patients with Alzheimer’s disease and serves as a biochemical marker for a pre-mortem diagnostic test for related diseases. 14-3-3 stabilizes ataxin-1, a polyQ protein found in SCA1 and other triplet repeat disorders such as Huntington’s disease, Parkinson’s disease, and others. Thus, understanding the mechanisms that control 14-3-3 ligand interactions will provide insight into more general questions concerning the control of intracellular signal transduction. Some crystal structures of 14-3-3 isoforms are known. This research aims to determine the tertiary structures of unknown isoforms by homology models and study behaviors of 14-3-3 isoforms by protein-protein interactions and their dimerization properties. Such studies will be highly useful for developing therapeutics for these rare diseases.