The Effect of Lithium Binding on Secondary and Tertiary Structure, Hydrophobicity, Thermodynamics, and Interactions with Interacting Partners of Dream

Abstract

Li+ is widely used for the treatment of manic-depressive illness. Studies on neuronal calcium sensor protein1 (NCS-1) have found that Li+ can inhibit the interaction between NCS-1 and inositol 1,4,5-triphosphate receptor protein, alleviating hyperarousal of insomnia patient. Li+ can have neuroprotective or neurotoxic effects depending on its concentration. In a rat model, chronic exposure to Li+ has shown a significant decrease in membrane-associated protein kinase C (PKC) in the hippocampus, suggesting potential clinical relevance. Here, we show that Li+ binds to a neuronal calcium sensor protein named Downstream Element Antagonist Modulator (DREAM), a protein homologous to NCS-1 and expressed in the hippocampus region of the brain. Li+ association results in a decrease in the emission intensity of tryptophan, suggesting rearrangements of the tertiary structure of the protein. Li+ binding also exposes hydrophobic cavity of the protein as evidenced by binding of the hydrophobic molecule 1,8-ANS. CD data reveal that Li+ binding alters the protein secondary structure. Tryptophan emission and CD data are further supported by steady-state lifetime data. Thermodynamic parameters for Li+ association to DREAM have been obtained through isothermal titration calorimetry (ITC) measurements. Li+-bound DREAM interactions with binding partners have been probed by titrating FITC-tagged presenilin-1 and potassium channel against Li+-bound DREAM. Findings of this project suggest potentials for the Li+-based compounds in the animal model to investigate whether acute and chronic exposure to Li+ has any effect on the expression level of DREAM and whether Li+-based compounds influence interactions between DREAM and intracellular partners.