The long-term goal of this research is to elucidate the molecular and cellular mechanisms that ensure potassium (K+) channels assemble with the appropriate membrane-embedded regulatory subunits for proper physiological function. N-glycosylation is a vital co- and post-translational modification that facilitates the assembly and trafficking of K+ channel subunits. Mutations that block glycosylation of KCNE K+ regulatory subunits have been directly linked to the genetic and drug-induced forms of cardiac arrhythmias (Long QT Syndrome). Accordingly, the two aims of this proposal investigate K+ channel subunit glycosylation in the ER, Golgi and plasma membrane: (1) We will determine the molecular and cellular bases of K+ channel subunit co- and post-translational N-glycosylation. (2) We will reengineer the cell's glycocalyx to fluorescently visualize K+ efflux from living cells.
Potassium (K+) channels function as macromolecular protein complexes composed of membrane-embedded ion-conducting and regulatory subunits. Mutations that prevent the assembly, trafficking or function of these complexes give rise to neurological, cardiac, muscular, auditory, and respiratory diseases. By investigating the molecular and cellular mechanisms that ensure the assembly, trafficking and function of K+ channel complexes, we aim to understand how these proteins work in healthy individuals and provide alternative strategies for remedying those affected by channelopathies (ion channel-related diseases).
| Kobertz, William R (2018) Oddballs in the Shaker family: Kv2-related regulatory subunits. J Gen Physiol 150:1599-1601 |
| Bandara, H M Dhammika; Hua, Zhengmao; Zhang, Mei et al. (2017) Palladium-Mediated Synthesis of a Near-Infrared Fluorescent K+ Sensor. J Org Chem 82:8199-8205 |
| Kubat Öktem, Elif; Mruk, Karen; Chang, Joshua et al. (2016) Mutant SOD1 protein increases Nav1.3 channel excitability. J Biol Phys 42:351-70 |
| Zhang, Lejie; Bellve, Karl; Fogarty, Kevin et al. (2016) Fluorescent Visualization of Cellular Proton Fluxes. Cell Chem Biol 23:1449-1457 |
| Mruk, Karen; Kobertz, William R (2015) Bioreactive Tethers. Adv Exp Med Biol 869:77-100 |
| Malaby, Heidi L H; Kobertz, William R (2014) The middle X residue influences cotranslational N-glycosylation consensus site skipping. Biochemistry 53:4884-93 |
| Kobertz, William R (2014) Stoichiometry of the cardiac IKs complex. Proc Natl Acad Sci U S A 111:5065-6 |
| Aromolaran, Ademuyiwa S; Subramanyam, Prakash; Chang, Donald D et al. (2014) LQT1 mutations in KCNQ1 C-terminus assembly domain suppress IKs using different mechanisms. Cardiovasc Res 104:501-11 |
| Mruk, Karen; Farley, Brian M; Ritacco, Alan W et al. (2014) Calmodulation meta-analysis: predicting calmodulin binding via canonical motif clustering. J Gen Physiol 144:105-14 |
| Malaby, Heidi L H; Kobertz, William R (2013) Molecular determinants of co- and post-translational N-glycosylation of type I transmembrane peptides. Biochem J 453:427-34 |
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