Zinc plays a crucial role in development, particularly in the brain where it is found at high concentrations. Zinc levels must be tightly controlled as disruption of zinc homeostasis has been linked to a variety of disorders ranging from Alzheimer's disease to ischemia induced by cerebral stroke to schizophrenia. Most zinc in the brain is found bound to proteins, including zinc finger transcription factors. Two zinc finger transcription factors that play a crucial role in neuronal development are Neural Zinc Finger Factor-1 (NZF-1) and Myelin Transcription Factor 1 (MyT1). These proteins are essential for the development of neurons and oligodendrocytes, respectively and misregulation of these proteins has been associated brain cancer, schizophrenia, and mental retardation. Despite their importance in neuronal development, relatively little is known about the structure/function of these proteins. Both NZF-1 and MyT1 contain multiple, homologous zinc binding domains yet recognize and regulate completely different genes. This proposal is aimed at identifying the factors that enable the two proteins to regulate different genes and at understanding the mechanism of zinc mediated DNA recognition. The following two aims are proposed: 1) What are the roles of the 5 zinc finger domains in NZF-1? and 2) What are the roles of the 6 zinc finger domains in MyT1 and how do these differ from those of NZF-1? A systematic approach, using biochemical and biophysical methodologies, will be taken. Understanding the fundamental biochemical and biophysical properties of these proteins will be a first step towards understanding how these highly homologous transcription factors function to regulate neuronal development and provide key insights into how misregulation may lead to neurological disorders.

Public Health Relevance

Neural Zinc Finger Factor-1 (NZF-1) and Myelin Transcription Factor 1 (MyT1) are proteins involved in neuronal development that have been implicated in a variety of disorders, yet little is known about their structure or function. Understanding the mechanisms by which these two important proteins regulate DNA will be an important step towards understanding how these proteins regulate the development of the brain and central nervous system (CNS).

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F04B-D (20))
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Riddle, Robert D
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University of Maryland Baltimore
Schools of Pharmacy
United States
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Besold, Angelique N; Widger, Leland R; Namuswe, Frances et al. (2016) Revisiting and re-engineering the classical zinc finger peptide: consensus peptide-1 (CP-1). Mol Biosyst 12:1183-93
Besold, Angelique N; Amick, Deborah L; Michel, Sarah L J (2014) A role for hydrogen bonding in DNA recognition by the non-classical CCHHC type zinc finger, NZF-1. Mol Biosyst 10:1753-6
Besold, Angelique N; Oluyadi, Abdulafeez A; Michel, Sarah L J (2013) Switching metal ion coordination and DNA Recognition in a Tandem CCHHC-type zinc finger peptide. Inorg Chem 52:4721-8