The rise in obesity worldwide parallels a dramatic increase in obesity-associated diseases, most notably type-II diabetes. This disease is predicted to reach epidemic proportions in the next several decades. Thus, understanding the biochemical processes underlying type-II diabetes and identifying new targets for therapeutic intervention are critical for national and world health. Some of the most widely prescribed insulin-sensitizing drugs to treat type-II diabetes belong to the thiazolidinedione (TZD) class of molecules. These drugs were found to also reduce many of the pathologies related to metabolic syndrome including hypertension, abdominal obesity, coronary artery inflammation, multiple sclerosis, Alzheimer's disease and Amyotrophic lateral sclerosis. While the TZDs were originally thought to exert their effects solely through activation of the nuclear transcription factor PPAR?, it is nw known that many of the beneficial effects are mediated in a PPAR?-independent manner. The TZDs were recently shown to interact with a novel mitochondrial protein target called mitoNEET. We reported that the protein mitoNEET is a redox-active, pH-labile 2Fe-2S cluster containing protein in the outer mitochondrial membrane. This is the only known Fe-S protein in the outer mitochondrial membrane. In addition, we discovered that MitoNEET plays an important role in iron management under oxidative stress conditions. Miner1, an endoplasmic reticulum homolog of mitoNEET, is important in maintaining health and longevity and interacts with proteins associated with cancer as well as neurodegenerative diseases. These proteins have emerged as important new therapeutic targets in diseases ranging from diabetes to Alzheimer's. The focus of this proposal is the structural, biochemical and functional characterization of this novel protein family. Specifically, we are investigating the molecular determinants of drug binding as a function of changes in oxidation state and asking how drug binding impacts newly discovered protein-protein interactions that are involved in regulating cell survival and death processes. The proposed studies are of both fundamental significance in understanding this protein-drug recognition as well as the identification of novel therapeutics.

Public Health Relevance

Every thirty seconds someone loses a limb/ limb function as a result of complications from unregulated blood glucose levels. Complications associated with the traditional anti-diabetes targeted therapies underscores the need for a paradigm shift in thinking with respect to new drug development. The goals of this proposal are directed towards the structural/biochemical characterization of drug binding to the newly discovered anti- diabetes targets: the novel 2Fe-2S proteins MitoNEET and Miner1.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM101467-02
Application #
8549271
Study Section
Special Emphasis Panel (ZRG1-BCMB-S (02))
Program Officer
Anderson, Vernon
Project Start
2012-09-21
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$276,874
Indirect Cost
$93,524
Name
University of California San Diego
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Pesce, Luca; Calandrini, Vania; Marjault, Henri-Baptiste et al. (2017) Molecular Dynamics Simulations of the [2Fe-2S] Cluster-Binding Domain of NEET Proteins Reveal Key Molecular Determinants That Induce Their Cluster Transfer/Release. J Phys Chem B 121:10648-10656
Yim, Kendrick H; Prince, Thomas L; Qu, Shiwei et al. (2016) Gambogic acid identifies an isoform-specific druggable pocket in the middle domain of Hsp90?. Proc Natl Acad Sci U S A 113:E4801-9
Holt, Sarah H; Darash-Yahana, Merav; Sohn, Yang Sung et al. (2016) Activation of apoptosis in NAF-1-deficient human epithelial breast cancer cells. J Cell Sci 129:155-65
Darash-Yahana, Merav; Pozniak, Yair; Lu, Mingyang et al. (2016) Breast cancer tumorigenicity is dependent on high expression levels of NAF-1 and the lability of its Fe-S clusters. Proc Natl Acad Sci U S A 113:10890-5
Keshwani, Malik M; Aubol, Brandon E; Fattet, Laurent et al. (2015) Conserved proline-directed phosphorylation regulates SR protein conformation and splicing function. Biochem J 466:311-22
Bai, Fang; Morcos, Faruck; Sohn, Yang-Sung et al. (2015) The Fe-S cluster-containing NEET proteins mitoNEET and NAF-1 as chemotherapeutic targets in breast cancer. Proc Natl Acad Sci U S A 112:3698-703
Barkho, Sulyman; Pierce, Levi C T; Li, Sheng et al. (2015) Correction: Theoretical Insights Reveal Novel Motions in Csk's SH3 Domain That Control Kinase Activation. PLoS One 10:e0133801
Daniel, Kevin B; Sullivan, Eric D; Chen, Yao et al. (2015) Dual-Mode HDAC Prodrug for Covalent Modification and Subsequent Inhibitor Release. J Med Chem 58:4812-21
Lipper, Colin H; Paddock, Mark L; Onuchic, José N et al. (2015) Cancer-Related NEET Proteins Transfer 2Fe-2S Clusters to Anamorsin, a Protein Required for Cytosolic Iron-Sulfur Cluster Biogenesis. PLoS One 10:e0139699
Barkho, Sulyman; Pierce, Levi C T; Li, Sheng et al. (2015) Theoretical Insights Reveal Novel Motions in Csk's SH3 Domain That Control Kinase Activation. PLoS One 10:e0127724

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