Understanding the Transcriptional and Translational Regulatory Roles of Non-Classical Neural Zinc Finger Proteins Involved in the Development of the Nervous System

Abstract

Zinc plays a crucial role in the development of the nervous system. Disruption of zinc homeostasis results in several nervous system disorders, including cerebral stroke, Alzheimer's disease, schizophrenia, mental retardation, periventricular leukomalacia, and brain cancer. Two ‘zinc finger’ proteins, Neural Zinc Finger Factor-1 (NZF-1) and Myelin Transcription Factor 1 (MyT1), play key roles in the development of the nervous system: NZF-1 regulates the development of neurons and MyT1 regulates the development of oligodendrocytes. Both proteins contain clusters of highly homologous yet modular CCHHC domains that can selectively recognize/regulate different genes when zinc is coordinated to the domains. The mechanisms of zinc mediated DNA recognition by these proteins is not well understood. Using a combination of biochemical, biophysical and spectroscopic approaches, including fluorescence anisotropy, NMR spectroscopy and mass spectrometry, we have begun to map out the key interactions that drive molecular recognition and we will present a current model for these recognition events. In addition, we will present evidence that a novel Co-Schiff base complex inhibits the function of NZF-1, by disrupting the zinc coordination and accompanying folding of the CCHHC domains. This complex has the potential to be used as a functional probe and small molecule inhibitor of NZF-1.