Dax Fu

Brookhaven National Laboratory
Bldg. 463 - P.O. Box 5000
Upton, NY 11973-5000

Recent News

Research Interests

Metals are essential elements for life. About one third of proteins in any living cell need metals to drive enzymatic catalysis, organize protein structures, and mediate macromolecular interactions. At the heart of the cellular metal metabolism are the metal-transporting proteins that move metal ions across biological membranes. By regulating metal fluxes, metal uptake and efflux transporters establish a delicate flow-equilibrium of metal ions to enable a myriad of cellular processes, such as DNA replication and hormone secretion.

We seek to understand the physicochemical principles governing the selectivity and energetics of metal transporters by an integrated approach of membrane biochemistry, structural biology and metallochemistry. Our biochemical studies have shown that the binding affinity of a zinc transporter is much lower than expected for effective Zn(II) equilibrium binding in vivo. On the other hand, the timescale of Zn(II) transport is millisecond, vastly faster than most metalloproteins that typically take hours to release bound Zn(II). It is not clear how the protein structures are built around zinc coordination chemistry to achieve this remarkable thermodynamic-kinetic capacity.

To answer this question, we have developed metal transport assays with millisecond time-resolution, and determined the crystal structure of a zinc transporter at atomic resolution. Our structure suggests how zinc coordination chemistry is coupled with protein dynamics to allow a rapid passage of zinc ions across the membrane barrier, while retaining an extraordinary metal selectivity over similar metal ions several orders of magnitude more abundant in vivo.

Our current research is focusing on a pair of complementary zinc uptake and efflux transporters, known as ZIP and CDF, respectively. We use a battery of synchrotron-based techniques to explore protein structures and their conformational dynamics in real time.

The structures of GlpF and YiiP have been solved by MIR/AS/AD phasing at 2.2 and 3.8 Å resolution respectively, while AqpZ was solved by molecular replacement at 3.2 Å resolution.

Selected Publications

• Lin W., Chai J., Love J. and Fu D.
  Selective electrodiffusion of zinc ions in a Zrt-, Irt-like protein, ZIPB.
  J Biol Chem., 285(50):39013-20 (2010).  PubMed
• Lu M., Chai J. and Fu D.
  Structural basis for autoregulation of the zinc transporter YiiP.
  Nat. Struct. Mol. Biol., 16(10):1063-1067 (2009).  PubMed
• Lu M. and Fu D.
  Structure of the zinc transport YiiP.
  Science, 317:1746-8 (2007).  PubMed  Full Text
  See also: Science Perspective by DH Nies: Science 317:1695-1696 (2007).
• Fu D. and Lu M.
  The structural basis of water permeation and proton exclusion in aquaporins (Review).
  Mol Membr Biol., 24(5):366-374 (2007).  PubMed  Full Text
• Wei Y. and Fu D.
  Binding and transport of metal ions at the dimer interface of the Escherichia coli metal transporter YiiP.
  J Biol Chem., 281(33):23492-23502 (2006).  PubMed  Full Text
• Jiang J., Daniels B.V. and Fu D.
  Crystal structure of AqpZ tetramer reveals two distinct Arg-189 conformations associated with water permeation through the narrowest constriction of the water-conducting channel.
  J Biol Chem., 281(1):454-460 (2006).  PubMed  Full Text  PDB file: 2ABM  Jmol viewer
• Wei Y. and Fu D.
  Selective metal binding to a membrane-embedded aspartate in the Escherichia coli metal transporter YiiP (FieF).
  J Biol Chem., 280(40):33716-33724 (2005).  PubMed  Full Text
• Wei Y., Li H. and Fu D.
  Oligomeric state of the Escherichia coli metal transporter YiiP.
  J Biol Chem., 279(38):39251-39259 (2004).  PubMed  Full Text
• Chao Y. and Fu D.
  Thermodynamic studies of the mechanism of metal binding to the Escherichia coli zinc transporter YiiP.
  J Biol Chem., 279(17):17173-17180(2004).  PubMed  Full Text
• Chao Y and Fu D.
  Kinetic study of the antiport mechanism of an Escherichia coli zinc transporter, ZitB.
  J Biol Chem., 279(13):12043-12050 (2004).  PubMed  Full Text 
• Fu D., Libson A., Miercke L.J., Weitzman C., Nollert P., Krucinski J. and Stroud R.M.
  Structure of a glycerol-conducting channel and the basis for its selectivity.
  Science, 290:481-486 (2000).  PubMed  Full Text  PDB file: 1FX8  Jmol viewer

Last Modified: September 15, 2011
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One of ten national laboratories overseen and primarily funded by the Office of Science of the U.S. Department of Energy (DOE), Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies and national security. Brookhaven Lab also builds and operates major scientific facilities available to university, industry and government researchers. Brookhaven is operated and managed for DOE's Office of Science by Brookhaven Science Associates, a limited-liability company founded by Stony Brook University, the largest academic user of Laboratory facilities, and Battelle, a nonprofit, applied science and technology organization.

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