NMR structure of inactivation gates from mammalian voltage-dependent potassium channels

• Published in: Nature (London) Vol. 385; no. 6613; pp. 272 - 275
• Main Authors: Antz, Christof, Geyer, Matthias, Fakler, Bernd, Schott, Markus K, Guy, H. Robert, Frank, Rainer, Ruppersberg, Johann Peter, Kalbitzer, Hans Robert
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 16.01.1997; Nature Publishing Group
• Subjects: Amino Acid Sequence; Animals; Biological and medical sciences; Cell membranes. Ionic channels. Membrane pores; Cell structures and functions; Electrochemistry; Fundamental and applied biological sciences. Psychology; Inactivation; Ion Channel Gating; Magnetic Resonance Spectroscopy; Mammals; Models, Molecular; Molecular and cellular biology; Molecular Sequence Data; NMR; Nuclear magnetic resonance; Peptide Fragments - chemistry; Peptides; Potassium; Potassium Channels - chemistry; Protein Conformation; Spatial distribution; Spectroscopy; Structure-Activity Relationship; Membrane protein; Molecular structure; Nervous system; Ionic channel; NMR spectrometry; Inactivation; Vertebrata; Regulation(control); Mammalia; Neuron; Domain structure; Molecular domain; Potassium
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/385272a0

The electrical signalling properties of neurons originate largely from the gating properties of their ion channels. N-type inactivation of voltage-gated potassium (Kv) channels is the best-understood gating transition in ion channels, and occurs by a 'ball-and-chain' type mechanism. In this mechanism an N-terminal domain (inactivation gate), which is tethered to the cytoplasmic side of the channel protein by a protease-cleavable chain, binds to its receptor at the inner vestibule of the channel, thereby physically blocking the pore. Even when synthesized as a peptide, ball domains restore inactivation in Kv channels whose inactivation domains have been deleted. Using high-resolution nuclear magnetic resonance (NMR) spectroscopy, we analysed the three-dimensional structure of the ball peptides from two rapidly inactivating mammalian K. channels (Raw3 (Kv3.4) and RCK4 (Kv1.4)). The inactivation peptide of Raw3 (Raw3-IP) has a compact structure that exposes two phosphorylation sites and allows the formation of an intramolecular disulphide bridge between two spatially close cysteine residues. Raw3-IP exhibits a characteristic surface charge pattern with a positively charged, a hydrophobic, and a negatively charged region. The RCK4 inactivation peptide (RCK4-IP) shows a similar spatial distribution of charged and uncharged regions, but is more flexible and less ordered in its amino-terminal part.