William Kobertz, Ph.D.

Academic Role: Associate Professor

Faculty Appointment(s) In:
   Biochemistry and Molecular Pharmacology

Other Affiliation(s):
   Interdisciplinary Graduate Program
   Program in Neuroscience

Structure, Function and Modulation of Ion Channels.

Ion channels are the proteins that create the electricity in all living cells. Although a solitary ion channel protein possesses the machinery to generate an electrical signal, cells have evolved membrane-embedded partner proteins that associate with and fine-tune the electrical currents of ion channels to achieve the appropriate physiological function for that particular cell. The rhythmicity of the heart beat, maintenance of arterial tone and insulin release by b cells in the pancreas are all physiological processes that require a healthy association between ion channel and partner protein.

Our laboratory is investigating the structural motifs of these membrane-embedded protein-protein interactions as well as the molecular basis for the dramatic changes in ion channel function due to this association. Armed with this structural data, we aim to construct novel partner proteins and potentially small organic molecules designed to modulate ion channel function. One basic question the lab is interested in is how do two hydrophobic proteins selectively associate in the greasy confines of the membrane where the "hydrophobic effect" that usually brings water-soluble proteins together presumably cannot operate? By studying the ion channel/partner protein complex at the molecular level we hope to improve our current primitive understanding of membrane-embedded protein-protein interactions.

Because the study of membrane proteins poses unique challenges in protein biochemistry, the lab is developing lipomimetic reagents that specifically target proteins in the cellular membrane. We also rely on the powerful techniques of electrophysiology including single-channel recording, two-electrode voltage-clamp and the Xenopus ooctye expression system to address these structural, biophysical and physiological questions.

Representative Publications

Mruk K and Kobertz WR.  (2009) Discovery of a Novel Activator of KCNQ1-KCNE1 K+ Channel Complexes .  PLoS ONE 4, e4236.

Ahern CA and Kobertz WR.  (2009) Chemical Tools for K+ Channel Biology .  Biochemistry 48, 517-526.

Morin TJ and Kobertz WR.  (2008) Tethering chemistry and K+ Channels.    J. Biol. Chem. 283, 25105-25109.

Morin TJ and Kobertz WR  (2008)  Counting Membrane-embedded KCNE b-subunits in Functioning K+ Channel Complexes.   Proc. Natl. Acad. Sci. USA.  105, 1478-1482.

Rochelau JM and Kobertz WR.  (2008)   KCNE Peptides Differently Affect Voltage Sensor Equilibrium and Equilibration Rates in KCNQ1 K+ Channels.   J. Gen. Physiol. 131, 59-68. 

Morin TJ and Kobertz WR.  (2007)  A Derivatized Scorpion Toxin Reveals the Functional Output of Heteromeric KCNQ1-KCNE K+ Channel Complexes.   ACS Chem Biol. 2, 469-473.  (Point of View / July 2007 Podcast )

Chandrasekhar KD, Bas T and Kobertz WR. (2006)  KCNE1 Subunits Require Co-assembly with K+ Channels for Efficient Trafficking and Cell Surface Expression.    J. Biol. Chem. 281, 40015-40023.

Rocheleau JM, Gage SD and Kobertz WR. (2006)  Secondary structure of a KCNE cytoplasmic domain.   J. Gen. Physiol. 128, 721-729.

Gage, SD and Kobertz WR.  (2004)  KCNE3 Truncation Mutants Reveal a Bipartite Modulation of KCNQ1 K+ Channels. J. Gen. Physiol. 124, 759-771.

Kobertz, WR, Williams, C and Miller, C. (2000)  Hanging Gondola Structure of the T1 Domain in a Voltage-gated K+ channel.   Biochemistry 39, 10347-10352.

Kobertz, WR and Miller, C. (1999)  K+ Channels Lacking the "Tetramerization" Domain: Implications for Pore Structure.   Nat. Struct. Biol. 6, 1122-1125.

Potential Rotation Projects

Project #1.  Mapping K⁺ channel—partner protein interactions:  Some K⁺ channels must co-assemble with membrane-embedded b-subunits for proper physiological function.  In this project, we are mapping the protein-protein interactions between the KCNQ1 K⁺ channel and a family of transmembrane peptides:  the KCNEs.  To map out these protein-protein interactions, several different techniques will be used.  These include, but are not limited to, membrane protein biochemistry, chemical modification, and electrophysiology.

Project #2.   Assembly and trafficking of K⁺ channel complexes:  Efficient assembly and trafficking of K⁺ channel complexes is critical for physiological function.  Several mutations that prevent the assembly and trafficking of the KCNQ1-KCNE1 K⁺ channel complex give rise to cardiac arrhythmias and congenital deafness.  This rotation project involves measuring the rates of ER-exit, cell surface internalization and recycling of wild type and mutant K⁺ channel complexes.  These rates will be measured using cell surface and pulse-chase labeling methods.  Immunofluorescence will also be utilized for visualization and co-localization of K⁺ channel complexes in fixed and living cells.

Project #3.   Synthesis of Small Molecules for probing K⁺ channel structure and function:  Several basic structure/function questions remain with K⁺ channel complexes:  (1) What is the stoichiometry of a functioning complex? (2)  Do multiple KCNE partnering proteins assemble with one K⁺ channel?  (3) Do sub- or super-stoichiometric complexes exist?  For this rotation project, we are synthesizing novel small molecule probes and using them in combination with electrophysiology to address these and other basic structural questions about K⁺ channel complexes.

Laboratory Staff

Academic Background

William Kobertz received his Ph.D. (1997) from the Department of Chemistry at MIT. He was a Howard Hughes postdoctoral fellow with Christopher Miller at Brandeis University from 1998-2001. Following his postdoctoral work, he joined the Department of Biochemistry and Molecular Pharmacology at the University of Massachusetts Medical School as a faculty member and is also a recipient of a Burroughs Wellcome Career Award in the Biomedical Sciences (2001-2005).

Office: LRB 804, lab 840A-C
Phone: 508-856-8861
E-mail: William.Kobertz@umassmed.edu
Keywords: Biophysics, Ion Channels, Biochemistry, Membrane Protein Structure & Function, Chemical Biology

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