B.S. Seoul National University, Chemical Engineering
M.S. Seoul National University, Biological Sciences
Ph.D. Harvard University, Biological Chemistry & Molecular Pharmacology
CLC proteins are ubiquitous membrane proteins that transport chloride ions across membranes. They are involved in various biological processes including regulation of membrane potential, cell volume homeostasis, electrolyte/fluid transport across epithelia, and control of intravesicular pH and chloride concentration. Mutations in CLC genes cause many hereditary disorders in humans, such as myotonia congenita, Dent’s disease, Bartter’s syndrome, osteopetrosis, and lysosomal storage diseases.
One of the most interesting aspects of CLC proteins is that a common structural architecture seems to be used for both active and passive ion transport. Some CLC proteins are chloride channels, which provide a passive pore for chloride ion conduction across membranes, whereas others function as secondary active transporters that exchange two chloride ions for one proton. This surprising feature challenges the prevalent traditional concept that channels and transporters have largely unrelated structures.
Despite recent advances in our understanding of how CLC proteins operate, fundamental questions remain unanswered. These include how exactly CLC transporters couple the transfer of chloride and protonions and what is the structural basis of CLC channel function. The second question, in particular, has remained elusive because structures of only transporter versions of CLC proteins have so far been determined. In the MacKinnon lab, I use structural and functional approaches to address these questions.
References:
Dutzler R, Campbell EB, Cadene M, Chait BT & MacKinnon R (2002) X-ray structure of a ClC chloride channel at 3.0 A reveals the molecular basis of anion selectivity. Nature 415, 287-294.
Dutzler R, Campbell EB & MacKinnon R (2003) Gating the selectivity filter in ClC chloride channels. Science 300, 108-112.
Feng L, Campbell EB, Hsiung Y & MacKinnon R (2010) Structure of a eukaryotic CLC transporter defines an intermediate state in the transport cycle. Science 330, 635-641.
Feng L, Campbell EB & MacKinnon R (2012) Molecular mechanism of proton transport in CLC Cl-/H+ exchange transporters. Proc Natl Acad Sci U S A 109, 11699-11704.
