Membrane Transport Biophysics Section - Division of Intramural Research

Joseph A. Mindell, M.D., Ph.D., Senior Investigator

Laboratory Staff

Research Interests

The Membrane Transport Biophysics Unit focuses on understanding the physical principles governing membrane-protein function. Our major model proteins are members of the ClC family of anion-transport proteins. Use a combination of biochemical and physiological approaches, we seek to understand the protein elements mediating chloride selectivity as well as those involved in regulating the passage of ions across the membrane. Recent developments, including the determination of a high-resolution structure of a bacterial ClC, have allowed us to focus our attention on particular regions of these proteins, which we explore with combinations of biochemistry, genetic mutation, and electrical recordings.

Currently, we are using fluorescence-based methods to determine the nature and magnitude of conformational changes involved in the transport mechanism of ClC-ec1. We also measure the chloride and proton fluxes through these transporters using electrical recordings in lipid bilayer membranes as a means to probe the functional behavior of these proteins.

We are also interested in other transport proteins. Bacterial genome projects continue to reveal that these so-called ‘lower’ organisms express membrane proteins which are remarkably similar to their physiologically important mammalian cousins. Furthermore, compared to their ‘higher’ counterparts, these bacterial proteins are often more chemically stable and are easier to purify in large quantities, rendering them amenable to structural analysis. We have expressed several such proteins, and are pursuing more detailed analysis of their function and architecture.

Selected Recent Publications

• Compton ELR, Taylor EM, Mindell JA
  The 3-4 loop of an archael glutamate transporter homolog experiences ligand-induced structural changes and is essential for transport, PNAS, 2010, vol. doi/10.1073/pnas.1003046107
• Ryan RM, Compton, ELR, Mindell JA
  Functional characterization of a Na+-dependent aspartate transporter from Pyrococcus horikoshii., Journal of Biological Chemistry, 2009, vol. 284, pp. 17540-8.
• Osteen J and Mindell JA
  Insights into the ClC-4 transport mechanism from studies of Zn2+ inhibition., Biophysical Journal, 2008, vol. 95, pp. 4668-75.
• Graves AR. Curran PK, Smith CL, Mindell JA
  The Cl-/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes, Nature, 2008, vol. doi:10.1038/nature06907 Full Text/Abstract
• Ryan RM and Mindell JA
  The uncoupled chloride conductance of a bacterial glutamate, Nature Structural and Molecular Biology, 2007, vol. 14, pp. 365-71. Full Text/Abstract
• Bell SP, Curran PK, Choi S, and JA Mindell
  Site-directed fluorescence studies of a prokaryotic ClC transporter, Biochemistry, 2006, vol. 45, pp. 6773.
• Mindell JA, Maduke M, Miller C, Grigorieff N
  Projection structure of a ClC-type Cl- channel at 6.5 angstrom resolution, Nature, 2001, vol. 409, pp. 219. Full Text/Abstract
• Mindell JA
  Commentary: Swimming through the hydrophobic sea: New insights in protein translocation, Proc Natl Acad Sci U S A, 1998, vol. 95, pp. 4081. Full Text/Abstract

Selected Earlier Publications

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