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Christopher Miller, Ph.D.
Professor of Biochemistry
Investigator, Howard Hughes Medical Institute

Structure and Mechanism in Ion Channel Proteins

Ph.D., University of Pennsylvania

contact information
 (781) 736-2340

Our work here is aimed at understanding the molecular and structural underpinnings of the generation of cellular electricity. All such phenomena - from the nerve action potential, to sensory transduction, to control of processes as varied as muscle contraction, hormone secretion, or blood volume homeostasis - are ultimately mediated by a single class of membrane proteins: the ion channels. We seek to understand the molecular mechanisms by which ion channel proteins open and close to switch the flows of ions across cellular membranes, and by which the open pore is able to choose so exquisitely which ions are able to permeate.

The laboratory focuses on a broad class of ion channels - the CLC-type Cl- channels. These proteins are interesting because so little is known about them, despite the fact that high-resolution x-ray crystal structures are now known for some. The relationship between structure and functional behavior is an area of active investigation here, using bacterial CLC homologues and a combination of x-ray crystallography and electrophysiological analysis.

We recently discovered, to our shock and awe, that a bacterial homologue of this Cl- channel family is not itself an ion channel, but rather functions as an ion "pump," stoichiometrically exchanging Cl- on one side of the membrane for H+ on the other. Using a combination of electrophysiology, membrane reconstitution, and x-ray crystallography, we are endeavoring to understand how these ransport proteins work and also to comprehend the wider mechanistic implications of this co-habitation within the same molecular family of such fundamentally different ion-transport mechanisms.


Selected Publications

Iyer, R., Iverson, T.M., Accardi, A., and Miller, C. 2002. A biological role for prokaryotic ClC Cl- channels. Nature 419:715-718. [abstract]

Nimigean, C.M., Chappie, J.S., and Miller, C. 2003. Electrostatic tuning of ion conductance in K+ channels. Biochemistry 42:9263-9268. [abstract]

Accardi, A. and Miller, C. 2004. Secondary active transport mediated by a prokaryotic homologue of CLC Cl- channels. Nature 427:803-807. [abstract]

Nimigean, C.M., Shane, T., and Miller, C. 2004. A cyclic nucleotide modulated prokaryotic K+ channel. J Gen Physiol. 124:203-210. [abstract]

Posson, D.J., Ge, P. Miller, C. Bezanilla, F., and Selvin, P.R. 2005. Small vertical movement of a K+ channel voltage sensor measured with luminescence energy transfer. Nature 436:848-851. [abstract]

Miller, C. 2006. CLC chloride channels viewed through a transporter lens. Nature 440:484-489.

Nguitragool, W. and Miller, C. 2006. Uncoupling of a CLC Cl-/H+ exchange transporter by polyatomic anions. J. Mol. Biol. 362:682-690. [abstract]

Accardi, A., Lobet, S., Williams, C., Miller, C., and Dutzler, R. 2006. Synergism between halide binding and proton transport CLC-type exchanger. J. Mol. Biol. 362:691-699. [abstract]

Fang, Y., Kolmakova-Partensky, L., and Miller, C. 2007. A bacterial arginine-agmatine exchange transporter involved in extreme acid resistance. J. Biol. Chem. 282:176-182. [abstract]

Walden, M., Accardi, A.,Wu, F., Xu,C., Williams, C., and Miller, C. 2007. Uncoupling and turnover in a CLC Cl-/H+ exchanger. J. Gen. Physiol. 129:317-329. [abstract]

Nguitragool, W. and Miller, C. 2007.  CLC Cl-/H+ exchangers constrained by covalent cross-linking. Proc. Natl. Acad. Sci. USA 104:20659-20665. [abstract]

Jayaram, H., Accardi, A., Wu, F., Williams, C., and Miller, C. 2008. Ion permeation through a Cl--selective channel designed from a CLC Cl-/H+ exchanger.  Proc. Natl. Acad. Sci. USA 105: 11194-11199. [abstract]

Miller, C. and Nguitragool, W. 2009.  A provisional mechanism for Cl-/H+ exchange in CLC transport proteins. Phil. Trans. Roy. Soc. B. 364:175-180. [abstract]

Lim, H.H. and Miller, C. 2009. Intracellular proton-transfer mutants in a bacterial CLC Cl-/H+ exchanger.  J. Gen. Physiol. 133:131-138. [abstract]

View Complete Publication List on PubMed: Chris Miller

Last reviewed: June 6, 2008. E-mail comments or questions to the webmaster.

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