doyleetal - RESEARCH ARTICLES The Structure of the...

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The Structure of the Potassium Channel: Molecular Basis of K 1 Conduction and Selectivity Declan A. Doyle, Joa ˜o Morais Cabral, Richard A. Pfuetzner, Anling Kuo, Jacqueline M. Gulbis, Steven L. Cohen, Brian T. Chait, Roderick MacKinnon* The potassium channel from Streptomyces lividans is an integral membrane protein with sequence similarity to all known K 1 channels, particularly in the pore region. X-ray analysis with data to 3.2 angstroms reveals that four identical subunits create an inverted teepee, or cone, cradling the selectivity filter of the pore in its outer end. The narrow selectivity filter is only 12 angstroms long, whereas the remainder of the pore is wider and lined with hydrophobic amino acids. A large water-filled cavity and helix dipoles are positioned so as to overcome electrostatic destabilization of an ion in the pore at the center of the bilayer. Main chain carbonyl oxygen atoms from the K 1 channel signature sequence line the selectivity filter, which is held open by structural constraints to co- ordinate K 1 ions but not smaller Na 1 ions. The selectivity filter contains two K 1 ions about 7.5 angstroms apart. This configuration promotes ion conduction by exploiting electro- static repulsive forces to overcome attractive forces between K 1 ions and the selectivity filter. The architecture of the pore establishes the physical principles underlying selective K 1 conduction. P otassium ions diffuse rapidly across cell membranes through proteins called K 1 channels. This movement underlies many fundamental biological processes, includ - ing electrical signaling in the nervous sys - tem. Potassium channels use diverse mechanisms of gating (the processes by which the pore opens and closes), but they all exhibit very similar ion permeability characteristics ( 1 ). All K 1 channels show a selectivity sequence of K 1 Rb 1 . Cs 1 , whereas permeability for the smallest alkali metal ions Na 1 and Li 1 is immea - surably low. Potassium is at least 10,000 times more permeant than Na 1 , a feature that is essential to the function of K 1 channels. Potassium channels also share a constellation of permeability characteris - tics that is indicative of a multi - ion conduction mechanism: The flux of ions in one direction shows high - order cou - pling to flux in the opposite direction, and ionic mixtures result in anomalous con - duction behavior ( 2 ). Because of these properties, K 1 channels are classified as “long pore channels,” invoking the notion that multiple ions queue inside a long, narrow pore in single file. In addition, the pores of all K 1 channels can be blocked by tetraethylammonium (TEA) ions ( 3 ). Molecular cloning and mutagenesis ex - periments have reinforced the conclusion that all K 1 channels have essentially the same pore constitution. Without exception, all contain a critical amino acid sequence, the K 1 channel signature sequence. Muta - tion of these amino acids disrupts the chan - nel’s ability to discriminate between K 1 and Na 1 ions ( 4 ).
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This note was uploaded on 01/31/2011 for the course CBNS 120 taught by Professor Adams during the Winter '10 term at UC Riverside.

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doyleetal - RESEARCH ARTICLES The Structure of the...

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