Carol Deutsch
Professor, Dept of Physiology

Cell Biology and Physiology Program

Address

D200 Richards Bldg
3700 Hamilton Walk
Philadelphia, PA 19104

Office tel.: 215 898-8014
Fax: 215 573-5851
E-mail: cjd@mail.med.upenn.edu

Link(s)

Department of Physiology

Education

Brandeis University: BA (Chemistry), 1966.

Yale University: MPhil (Chemistry), 1969.

Yale University: PhD (Chemistry), 1972.

Research Interests

• Function and assembly of voltage-gated potassium channels.

Key words: voltage-gated K+ channels, C-type inactivation, gating kinetics, protein-protein interactions, oligomerization, channel assembly, biogenesis, ion channels, human T-lymphocytes.

Description of Research

The focus of my laboratory is molecular mechanisms underlying the assembly and function of voltage-gated potassium channels (Kv), with particular emphasis on Shaker channels and on Kv1.3, a channel in human T-lymphocytes. Kv channels have diverse and critical roles in both excitable and non-excitable cells. We use a range of approaches including biochemical, molecular biological, and electrophysiological techniques. The current projects are in two major areas: mechanisms of slow inactivation in Shaker K+ channels and biogenesis of Kv1.3.

Potassium channel activity in a cell depends on an ensemble of channel properties including permeation and gating. Permeant ions themselves modulate these properties, thereby suggesting a potential means of autoregulation of channel activity, which could be important for homeostatic electrical activity. Our long term goal is to understand the autoregulatory mechanisms by which permeant ions modulate and synergize pore properties, gating (specifically slow inactivation), and movement of the voltage sensor. Two main aims are pursued in the laboratory. The first aim investigates the mechanisms of permeant ion modulation of gating and permeation in potassium channels. Several hypotheses are considered by exploiting a series of Shaker mutants having different kinetics of slow inactivation. The second aim investigates whether ions in the selectivity filter modulate the movement of voltage sensors.

The second major area of investigation is devoted to elucidating the stepwise mechanisms by which a Kv channel acquires its secondary, tertiary, and quaternary structures. We are identifying key folding and oligomerization interactions in the N-terminal T1 domain and the pore region of Kv1.3 during biogenesis. In addition, we assess when, and in which compartment, secondary Kv conformations are achieved.

Recent Publications

Lu, J. and Deutsch, C. (2005). Folding zones inside the ribosomal exit tunnel. Nature Structural and Molecular Biology, 12, 1123-1129.

Ray, E.C. and Deutsch, C. (2006). A trapped intracellular cation modulates K+-chanen recovery from slow inactivation. Journal of General Physiology 128, 203-217.

Panyi, G. and Deutsch, C. (2006). Crosstalk between activation and slow inactivation gates of Shaker potassium channels. Journal of General Physiology, 128, 547-559.

Panyi, G. and Deutsch, C. (2007). Probing the cavity of the slow inactivated conformation of Shaker potassium channels. Journal of General Physiology 129, 403-418.

Tu, L., Wang, J., and Deutsch, C. (2007). Biogenesis of the T1-S1 Linker of Voltage-Gated K+ Channels. Biochemistry 468075-8084.

Lu, J., Kobertz, W.R., and Deutsch, C. (2007). Mapping the Electrostatic Potential within the Ribosomal Exit Tunnel. Journal of Molecular Biology (in press).

Search PubMed for more articles

Lab

Rotation Projects

1. Kv nascent peptide folds in the ribosomal exit tunnel. This is not a unilateral act by the peptide. The tunnel collaborates and is an active participant in translation. The precise mechanisms for this teamwork are unknown. In this aim, we will probe two aspects of this collaboration that are implicated by our recent studies: dynamic accessibilities and electrostatic potentials. We are the first to map both of these properties and demonstrate that both depend on the side-chains of residues in the elongating nascent peptide. We propose that an "accessibility wave", which may include peristalsis or flexing of the tunnel wall and/or reorientation of the nascent peptide occurs during translation. This wave is tuned to the unique primary sequence of each sojourning peptide. Two hypotheses will be addressed. First, peptide side-chain interactions with the tunnel have consequences for protein folding. Second, electrostatic potential gradients in the tunnel modulate kinetics of translation and folding of nascent Kv peptide. We will test these hypotheses using biochemical assays of translation, folding, and peptidyl-tRNA stability.
   
2. Secondary folding of nascent voltage-sensor segments. Two hypotheses will be addressed. First, transmembrane segments S1-S4 each acquire secondary structure in the ribosome or the translocon, prior to membrane insertion. Second, each segment is idiosyncratic: some segments of the voltage-sensor may compact in the ribosome and contain intrinsic helix-forming determinants, whereas others may not. To test these hypotheses, we will use accessibility assays that entail mass-tagging strategies.
   
3. Determine pore region architecture of Kv1.3 during biogenesis. We hypothesize that some of the tertiary structure of the pore is formed in the ribosome/translocon/Kv peptide complex. We use a folding assay to determine when and how pore architecture is established in the Kv nascent monomer and tetramer..

Lab personnel:

Andrey Kosolapov, Postdoctoral Fellow
Jianli Lu, Research Specialist
Christine Gajewski, Research Specialist
LiWei Tu, Senior Research Investigator