Structure-function relationships in heteromeric potassium channel complexes
There are forty known voltage-gated potassium channel alpha subunit genes in the human genome, helping to generate a rich diversity of voltage-gated potassium currents. Also contributing to this diversity are numerous types of ancillary, or beta, subunits - in fact, it is unlikely that voltage-gated potassium channels exist as pure homomeric channels in vivo. We study a family of five single transmembrane domain ancillary subunits called the MinK-related peptides (MiRPs, encoded by KCNE genes). MiRPs co-assemble with pore-forming potassium channel alpha subunits, forming heteromeric complexes with distinct functional features from their homomeric counterparts. One of the challenges in understanding these complexes is to determine which parts of each subunit perform which functions. Another goal is to understand the processes and protein sequence motifs that determine which alpha subunits interact with which ancillary subunits. A further aim is to identify what determines the disparate functional effects of regulation of each alpha subunit by each ancillary subunit. We are using site-directed mutagenesis combined with electrophysiological and biochemical techniques to determine structure-function relationships in alpha-MiRP potassium channel complexes. Relevant publications
Xu X, Kanda VA, Choi E, Panaghie G, Roepke TK, Gaeta SA, Christini DJ, Lerner DJ, Abbott GW. (2009) MinK-dependent internalization of the IKs potassium channel. Cardiovascular Research 82(3):430-8
Panaghie G, Purtell K, Tai KK, Abbott GW. Voltage-dependent C-type inactivation in a constitutively open K channel. Biophys J. 2008 95(6):2759-78 PMID: 18567635 Abbott GW, Ramesh B, Srai SK. Secondary structure of the MiRP1 (KCNE2) potassium channel ancillary subunit. Protein Pept Lett. 2008;15(1):63-75. PMID: 18221016 Panaghie G, Abbott GW. The role of S4 charges in voltage-dependent and voltage-independent KCNQ1 potassium channel complexes. J Gen Physiol. 2007 Feb;129(2):121-33. Epub 2007 Jan 16. PMID: 17227916 Panaghie, G., Tai, K.K., & Abbott G.W. Interaction of KCNE subunits with the KCNQ1 K channel pore. Journal of Physiology 570 (Pt 3):455-67, 2006 Abbott G.W., Butler, M.H., & Goldstein, S.A. Phosphorylation and protonation of neighboring MiRP2 sites: function and pathophysiology of MiRP2-Kv3.4 potassium channels in periodic paralysis. FASEB Journal 20(2):293-301, 2006 Panaghie, G., & Abbott G.W. The impact of ancillary subunits on small-molecule interactions with voltage-gated potassium channels. Current Pharmaceutical Design 12(18): 2285-2302, 2006 McCrossan ZA & Abbott G.W. The MinK-Related Peptides Neuropharmacology 47 (6) 787-821, 2004 Abbott G.W., Goldstein SA. Disease-associated mutations in KCNE potassium channel subunits (MiRPs) reveal promiscuous disruption of multiple currents and conservation of mechanism. FASEB J. 2002 Mar;16(3):390-400, 2002. Abbott G.W., Mercer, E.A.J., Miller, R.T., Ramesh, B. & Srai, S.K.S. Conformational changes in a mammalian voltage-dependent potassium channel inactivation peptide. Biochemistry 37 1640-1645, 1998 Mercer, E.A.J., Abbott G.W., Brazier, S., Ramesh, B., Haris, P.I. & Srai, S.K.S. Synthetic putative transmembrane region of minimal potassium channel protein (minK) adopts an alpha-helical conformation in phospholipid membranes. Biochemical Journal 325 (2) 475-9, 1997 Abbott G.W., Bloemendal, M., Van Stokkum, I.H.M., Mercer, E.A.J., Miller, R.T., Sewing, S., Wolters, M., Pongs, O. & Srai, S.K.S. Secondary structure, stability and tetramerisation of recombinant Kv1.1 potassium channel cytoplasmic N-terminal fragment. Biochim. Biophys. Acta 1341 71-78, 1997
