Eag domain-CNBHD complex of the mouse EAG1

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Introduction:

Mouse potassium voltage-gated channel subfamily H member 1 EAG homology domain (grey) complex with EAG domain (green) (PDB code 4llo)

The KCNH voltage-gated channels are transmembrane channels highly selective for potassium and sensitive to voltage changes in the cells’ membrane potential.

They play a crucial roles in repolarization of cells to their resting state and in various diseases such as cardiac long QT syndrome type 2 (LQT2)[1], epilepsy[2], schizophrenia[3] and cancer[4]. The KCNH channels family has unique intracellular domains that distinguish them from other voltage-gated channels. The amino terminal contains an eag domain and the C-terminus contains a cyclic nucleotide binding homology domain (CNBDH).


Intracellular domain structure of KCNH1 (mEAG):

KCNH channels have two intracellular domains that provide the unique properties of regulation and gating to this channel family. The CNBHD (residues 517-698) located on the C-terminus, however dose not bind cyclic nucleotides and regulates gating in unknown mechanism. The eag domain (residues 1-136) composed of a PAS domain (110 amino acid) and highly conserved PAS-cap (25 amino acid)[5]. The eag domain regulates the activation and inactivation in unknown mechanism[6]. The interface between the eag domain and the CNBHD is with an average buried solvent-accessible surface area of ~ (1,400 A ̊2)[7]. The interface consists of three sub-regions: (1) the intrinsic ligand motif of the CNBHD interacts with the aB-helix in the PAS domain; (2) the bA and bB strands of the PAS domain interact with the post-CNBHD segment of the CNBHD; and (3) an amphipathic helix (aCAP) in the PAS-cap domain forms an inter- action with the b-roll of the CNBHD[7]. The post CNBHD region has been shown to mediate the regulation of the channel by variety of cell signaling mediators, including phosphorylation, kinases and Ca2+-calmodulin[8],[9],[10]. The interaction between the eag domain and the post-CNBHD region suggests that KCNH channel regulation through the post-CNBHD region may involve its interaction interface with the eag domain[7].


Ca2+ Calmodulin (CaM) inhibition:

CaM is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells, and the binding of Ca2+ is required for its activation[11]. CaM binds EAG in the presence of Ca2+ and inhibits ion conduction[12],[13]. The mechanism is not fully understood. CNBHD – PAS domain complex has 3 CaM contact regions witch form 2 binding sites[13]. Two contact regions at the C-terminus of the CNBHD form 2 α-helices that act as a claw to grab the CaM C-lobe. The linker that connect the two lobes of CaM is very flexible thus he can break and allows the hydrophobic core of the CaM N-lobe to bind a helix on the PAS domain[14].


Disease:

The eag domain-CNBHD complex interface servers as a hot spot for many mutation associates with cancer and LQT2 (hERG).


Therapeutic potential:

The unique intracellular domains of KCNH family may be an orphan receptor. By finding ligands we may able to regulate these channels and stop these devastating conditions.



Reference:
  1. Sanguinetti, M. C. & Tristani-Firouzi, M. hERG potassium channels and cardiac arrhythmia. Nature 440, 463–469 (2006).
  2. Zhang, X. et al. Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nature Neurosci. 13, 1056–1058 (2010).
  3. Huffaker, S. J. et al. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nature Med. 15, 509–518 (2009).
  4. Camacho, J. Ether a` go-go potassium channels and cancer. Cancer Lett. 233, 1–9 (2006).
  5. Morais Cabral, J. H. et al. Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain. Cell 95, 649–655 (1998)
  6. Gustina, A. S. & Trudeau, M. C. HERG potassium channel regulation by the N-terminal eag domain. Cell. Signal. 24, 1592–1598 (2012)
  7. 7.0 7.1 7.2 Haitin, Y., A.E. Carlson, and W.N. Zagotta. 2013. The structural mechanism of KCNH-channel regulation by the eag domain. Nature
  8. Cherubini,A.etal.Humanether-a-go-go-relatedgene1channelsarephysically linked to b1 integrins and modulate adhesion-dependent signaling. Mol. Biol. Cell 16, 2972–2983 (2005)
  9. Sun,X.X.,Hodge,J.J.,Zhou,Y.,Nguyen,M.&Griffith,L.C.Theeagpotassium channel binds and locally activates calcium/calmodulin-dependent protein kinase II. J. Biol. Chem. 279, 10206–10214 (2004)
  10. Ziechner,U.etal.Inhibitionofhumanethera`go-gopotassiumchannelsby Ca21/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 273, 1074–1086 (2006)
  11. Stevens FC (1983). "Calmodulin: an introduction". Can. J. Biochem. Cell Biol. 61 (8): 906–10
  12. Schonherr R, Lober K, Heinemann SH. Inhibition of human ether a go-go potassium channels by Ca(2+)/calmodulin. EMBO J. 2000;19:3263–3271
  13. 13.0 13.1 Ziechner U, et al. Inhibition of human ether a go-go potassium channels by Ca2+/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 2006;273:1074–1086
  14. Jonathan R., Whicher Roderick MacKinnon. Structure of the voltage-gated K+ channel Eag1 reveals an alternative voltage sensing mechanism. Science. 2016 Aug 12; 353(6300): 664–669

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