Joseph A. Mindell, M.D., Ph.D.
Membrane Transport Biophysics Section
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.
- Nicoli ER, Weston MR, Hackbarth M, Becerril A, Larson A, Zein WM, Baker PR 2nd, Burke JD, Dorward H, Davids M, Huang Y, Adams DR, Zerfas PM, Chen D, Markello TC, Toro C, Wood T, Elliott G, Vu M, Undiagnosed Diseases Network., Zheng W, Garrett LJ, Tifft CJ, Gahl WA, Day-Salvatore DL, Mindell JA, Malicdan MCV. Lysosomal Storage and Albinism Due to Effects of a De Novo CLCN7 Variant on Lysosomal Acidification. Am J Hum Genet. 2019;104(6):1127-1138.
- Leray X, Hilton JK, Nwangwu K, Becerril A, Mikusevic V, Fitzgerald G, Amin A, Weston MR, Mindell JA. Tonic inhibition of the chloride/proton antiporter ClC-7 by PI(3,5)P2 is crucial for lysosomal pH maintenance. Elife. 2022;11.
- Graves AR, Curran PK, Smith CL, Mindell JA. The Cl-/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes. Nature. 2008;453(7196):788-92.
- Mulligan C, Fenollar-Ferrer C, Fitzgerald GA, Vergara-Jaque A, Kaufmann D, Li Y, Forrest LR, Mindell JA. The bacterial dicarboxylate transporter VcINDY uses a two-domain elevator-type mechanism. Nat Struct Mol Biol. 2016;23(3):256-63.
- Ryan RM, Mindell JA. The uncoupled chloride conductance of a bacterial glutamate transporter homolog. Nat Struct Mol Biol. 2007;14(5):365-71.
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This page was last updated on Wednesday, August 24, 2022