Da-Neng Wang

Da-Neng Wang, PhD

Skirball Institute

Professor, Department of Cell Biology

Keywords
biophysics, cancer, channels and transporters, metabolism, structural biology of membrane proteins
Summary

Membrane transporters and channels are amazing molecules in the cell. They function to control cellular homeostasis and a number of signaling processes, and are often direct targets for therapeutic agents. Our laboratory aims to understand the molecular mechanisms of these proteins using structural, biochemical & biophysical approaches. In 2010, we published the structures of the formate channel FocA from Vibrio cholerae, with and without formate ions bound (Nature Structural & Molecular Biology, 2010). FocA is a member of the formate-nitrite transport (FNT) family. The ion selectivity filter in FocA consists of a cytoplasmic slit and a central constriction ring. Interactions of the filter with bound formate ions provide a structural basis for the ion selectivity of the channel. The structures also suggest a possible gating mechanism in which movements of a cytosolic loop open and close the channel. This is the first time that both the ion selectivity and gating mechanism was understood for an organic-ion channel. More recently, we identified another subfamily of FNT proteins as being hydrosulfide channels and determined the crystal structure of the HSC protein from Clostridium difficile (Nature, 2012a).

Another system we work on is the Na+-driven tri- and dicarboxylate transporters in the plasma membrane. In human cells, cytosolic citrate is a major precursor for the synthesis of fatty acids, triacylglycerols, cholesterol and low-density lipoprotein. Cytosolic citrate further regulates the cell’s energy balance by activating the fatty acid synthesis pathway while down-regulating both the glycolysis and fatty acid β-oxidation pathways. The cytosolic citrate concentration partially depends on direct import across the plasma membrane via the Na+-dependent citrate transporter (NaCT). Mutations of the homologous fly gene (Indy, I’m Not Dead Yet) result in reduced fat storage through calorie restriction. NaCT-knockout mice show hepatic mitochondrial biogenesis, higher lipid oxidation and energy expenditure, and reduced lipogenesis, which taken together protect the mice from obesity and insulin resistance. To understand the transport mechanism of NaCT and INDY proteins, we recently determined the 3.2 Å crystal structure of a bacterial INDY homolog (Nature, 2012b). One citrate molecule and one sodium ion are bound per protein, and their binding sites are defined by conserved amino acid motifs forming the structural basis for understanding the transporters’ specificity. Comparison of the structure of the two symmetrical halves of the transporter suggests conformational changes that propel substrate translocation.

Phone

212-263-8634

Academic office

540 First Avenue

Third Floor, Lab 5

New York, NY 10016

Lab Website
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These focus areas and their associated publications are derived from medical subject headings from PubMed.
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Professor, Department of Cell Biology

PhD from Stockholm University

Kim, Kwangsoo; Mitra, Sharmistha; Wu, Gang; Berka, Vladimir; Song, Jinmei; Yu, Ye; Poget, Sebastien; Wang, Da-Neng; Tsai, Ah-Lim; Zhou, Ming

Biochemistry. 2016 Dec 06; 55(48):6673-6684

Karpowich, Nathan K; Song, Jinmei; Wang, Da-Neng

Journal of molecular biology. 2016 Jul 31; 428(15):3118-3130

Sauer, David B; Karpowich, Nathan K; Song, Jin Mei; Wang, Da-Neng

Biophysical journal. 2015 Oct 06; 109(7):1420-1428

Karpowich, Nathan K; Song, Jin Mei; Cocco, Nicolette; Wang, Da-Neng

Nature structural & molecular biology. 2015 Jul; 22(7):565-571

Mulligan, Christopher; Fitzgerald, Gabriel A; Wang, Da-Neng; Mindell, Joseph A

Journal of general physiology. 2014 Jun; 143(6):745-759

Science Communication: Quality at Stake [Letter]

Loew, Leslie M.; Wang, Da-Neng

Science. 2013 DEC 6; 342(6163):1169-1169

Waight, Andrew B; Czyzewski, Bryan K; Wang, Da-Neng

Current opinion in structural biology. 2013 Aug; 23(4):499-506

Karpowich, Nathan K; Wang, Da-Neng

Proceedings of the National Academy of Sciences of the United States of America (PNAS). 2013 Feb 12; 110(7):2534-2539