World map of former Miller trainees scattered to the winds

Much of 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 lab focuses mainly on two broad classes of ion channels - the K+ channels, which, though quite well-understood, offer intriguing opportunities to ask questions of ion selectivity, and CLC-type Cl- channels, which present several perplexing mechanistic puzzles still waiting to be solved. We use a combination of electrophysiological analysis, single-channel recording, membrane biochemistry, and x-ray crystallography to attack these problems, and students are expected to gain experience in all these approaches.

A few years ago, we discovered, to our shock and awe, that a bacterial homologue of CLC channels 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 transport 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.

We are also interested in rational engineering of membrane proteins, in order to understand details of the physical chemistry of protein folding within biological membranes.  How does a greasy transmembrane helix manage to specifically find its greasy protein partner, while at the same time avoiding the greasy lipids of the bilayer?  We are using two membrane proteins as test-beds to approach questions like this: the bacterial CLC, and AdiC, a bacterial arginine transporter whose structure we recently determined.

Selected Publications

Piasta, K.N., Theobald, D.L., and Miller, C. 2011. Potassium-selective block of barium permeation through single KcsA channels. J Gen Physiol 138:421-436. [abstract]

Clapham, D.E. and Miller, C. 2011. A thermodynamic framework for understanding temperature sensing by transient receptor potential (TRP) channels. Proc Natl Acad Sci U S A 108:19492-19497. [abstract]

Structure of a slow CLC Cl-/H+ antiporter from a cyanobacterium. Jayaram, H, Robertson, J.L. Wu, F., Williams, C., and Miller, C. 2011. Biochemistry 50:788-794. [abstract]

Design, function, and structure of a monomeric CLC transporter. Robertson, J., Kolmakova-Partensky, L., and Miller, C. 2010. Nature 468:844-847. [abstract]

Theobald, D.L. and Miller, C. News and Views: Surprises in structural sameness. Nature Struct. Mol. Biol. 2010. 17:2-3.

Miller C. CFTR: break a pump, make a channel. Proc Natl Acad Sci U S A. 2010 Jan 19;107(3):959-60. [abstract]

Miller C. Everything you always wanted to know about Sachs' seals. Biophys J. 2009 Aug 5;97(3):687. [abstract]

Fang, Y., Jayaram, H., Shane, T., Kolmakova-Partensky, L., Wu, F., Williams, C., Xiong, Y., and Miller, C. Structure of a prokaryotic virtual proton pump at 3.2 Å resolution. 2009. Nature 460:1040-1043. [abstract]

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

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

 

View Complete Publication List on PubMed: Chris Miller

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Last reviewed: January 12, 2012.