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    William R Kobertz PhD

    TitleAssociate Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentBiochemistry and Molecular Pharmacology
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB
    Worcester MA 01605
    Phone508-856-8861
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMD/PhD Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentNeuroscience

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentChemical Biology

        Overview 
        Narrative

        Structure, Function and Modulation of Ion Channels.

        Dr.  William Kobertz Ph.DIon 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.

        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).



        Rotation Projects

        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.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Malaby HL, Kobertz WR. Molecular determinants of co- and post-translational N-glycosylation of type I transmembrane peptides. Biochem J. 2013 Aug 1; 453(3):427-34.
          View in: PubMed
        2. Hua Z, Kobertz WR. Chemical derivatization and purification of Peptide-toxins for probing ion channel complexes. Methods Mol Biol. 2013; 995:19-30.
          View in: PubMed
        3. Mruk K, Shandilya SM, Blaustein RO, Schiffer CA, Kobertz WR. Structural insights into neuronal K+ channel-calmodulin complexes. Proc Natl Acad Sci U S A. 2012 Aug 21; 109(34):13579-83.
          View in: PubMed
        4. Gabriel L, Lvov A, Orthodoxou D, Rittenhouse AR, Kobertz WR, Melikian HE. The Acid-Sensitive, Anesthetic-Activated Potassium Leak Channel, KCNK3, Is Regulated By 14-3-3ß-Dependent, PKC-Mediated Endocytic Trafficking. J Biol Chem. 2012 Jul 30.
          View in: PubMed
        5. O'Connell D, Mruk K, Rocheleau JM, Kobertz WR. Xenopus laevis oocytes infected with multi-drug-resistant bacteria: implications for electrical recordings. J Gen Physiol. 2011 Aug; 138(2):271-7.
          View in: PubMed
        6. Bas T, Gao GY, Lvov A, Chandrasekhar KD, Gilmore R, Kobertz WR. Post-translational N-Glycosylation of Type I Transmembrane KCNE1 Peptides: IMPLICATIONS FOR MEMBRANE PROTEIN BIOGENESIS AND DISEASE. J Biol Chem. 2011 Aug 12; 286(32):28150-9.
          View in: PubMed
        7. Chandrasekhar KD, Lvov A, Terrenoire C, Gao GY, Kass RS, Kobertz WR. O-glycosylation of the cardiac IKs complex. J Physiol. 2011 Aug 1; 589(Pt 15):3721-30.
          View in: PubMed
        8. Hua Z, Lvov A, Morin TJ, Kobertz WR. Chemical control of metabolically-engineered voltage-gated K(+) channels. Bioorg Med Chem Lett. 2011 Sep 1; 21(17):5021-4.
          View in: PubMed
        9. Lvov A, Gage SD, Berrios VM, Kobertz WR. Identification of a protein-protein interaction between KCNE1 and the activation gate machinery of KCNQ1. J Gen Physiol. 2010 Jun; 135(6):607-18.
          View in: PubMed
        10. Ahern CA, Kobertz WR. Chemical tools for K(+) channel biology. Biochemistry. 2009 Jan 27; 48(3):517-26.
          View in: PubMed
        11. Mruk K, Kobertz WR. Discovery of a novel activator of KCNQ1-KCNE1 K channel complexes. PLoS One. 2009; 4(1):e4236.
          View in: PubMed
        12. Morin TJ, Kobertz WR. Tethering chemistry and K+ channels. J Biol Chem. 2008 Sep 12; 283(37):25105-9.
          View in: PubMed
        13. Morin TJ, Kobertz WR. Counting membrane-embedded KCNE beta-subunits in functioning K+ channel complexes. Proc Natl Acad Sci U S A. 2008 Feb 5; 105(5):1478-82.
          View in: PubMed
        14. Rocheleau JM, Kobertz WR. KCNE peptides differently affect voltage sensor equilibrium and equilibration rates in KCNQ1 K+ channels. J Gen Physiol. 2008 Jan; 131(1):59-68.
          View in: PubMed
        15. Morin TJ, Kobertz WR. A derivatized scorpion toxin reveals the functional output of heteromeric KCNQ1-KCNE K+ channel complexes. ACS Chem Biol. 2007 Jul 20; 2(7):469-73.
          View in: PubMed
        16. Rocheleau JM, Gage SD, Kobertz WR. Secondary structure of a KCNE cytoplasmic domain. J Gen Physiol. 2006 Dec; 128(6):721-9.
          View in: PubMed
        17. Chandrasekhar KD, Bas T, Kobertz WR. KCNE1 subunits require co-assembly with K+ channels for efficient trafficking and cell surface expression. J Biol Chem. 2006 Dec 29; 281(52):40015-23.
          View in: PubMed
        18. Gage SD, Kobertz WR. KCNE3 truncation mutants reveal a bipartite modulation of KCNQ1 K+ channels. J Gen Physiol. 2004 Dec; 124(6):759-71.
          View in: PubMed
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