Secondary literature sources for BTB
The following references were automatically generated.
- Cushman SJ, Nanao MH, Jahng AW, DeRubeis D, Choe S, Pfaffinger PJ
- Voltage dependent activation of potassium channels is coupled to T1 domain structure.
- Nat Struct Biol. 2000; 7: 403-7
- Display abstract
The T1 domain, a highly conserved cytoplasmic portion at the N-terminus of the voltage-dependent K+ channel (Kv) alpha-subunit, is responsible for driving and regulating the tetramerization of the alpha-subunits. Here we report the identification of a set of mutations in the T1 domain that alter the gating properties of the Kv channel. Two mutants produce a leftward shift in the activation curve and slow the channel closing rate while a third mutation produces a rightward shift in the activation curve and speeds the channel closing rate. We have determined the crystal structures of T1 domains containing these mutations. Both of the leftward shifting mutants produce similar conformational changes in the putative membrane facing surface of the T1 domain. These results suggest that the structure of the T1 domain in this region is tightly coupled to the channel's gating states.
- Biggin PC, Roosild T, Choe S
- Potassium channel structure: domain by domain.
- Curr Opin Struct Biol. 2000; 10: 456-61
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Since the determination of the structure of a bacterial potassium channel, the ion channel community has managed to gain momentum in the quest for a complete picture. The information is coming at a steady flow, on a domain by domain basis. Recent discoveries are starting to reveal clues to the complex manner in which potassium channels show enormous diversity of function and also to their methods of regulation. Currently, the structures of four domains are known, with the most recent addition being the Kvbeta structure. As efforts continue in the study of the transmembrane domains, especially the voltage-sensing apparatus, there has been a new realization with respect to the identification and role of the cytoplasmic domains in protein-protein interactions in particular. An additional discovery, considerably aided by recent genomic analysis, is that potassium channels comprising subunits with two pore regions and four transmembrane helices combined in a dimeric fashion are abundant and are probable targets for local anesthetics.
- Capener CE, Shrivastava IH, Ranatunga KM, Forrest LR, Smith GR, Sansom MS
- Homology modeling and molecular dynamics simulation studies of an inward rectifier potassium channel.
- Biophys J. 2000; 78: 2929-42
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A homology model has been generated for the pore-forming domain of Kir6.2, a component of an ATP-sensitive K channel, based on the x-ray structure of the bacterial channel KcsA. Analysis of the lipid-exposed and pore-lining surfaces of the model reveals them to be compatible with the known features of membrane proteins and Kir channels, respectively. The Kir6.2 homology model was used as the starting point for nanosecond-duration molecular dynamics simulations in a solvated phospholipid bilayer. The overall drift from the model structure was comparable to that seen for KcsA in previous similar simulations. Preliminary analysis of the interactions of the Kir6.2 channel model with K(+) ions and water molecules during these simulations suggests that concerted single-file motion of K(+) ions and water through the selectivity filter occurs. This is similar to such motion observed in simulations of KcsA. This suggests that a single-filing mechanism is conserved between different K channel structures and may be robust to changes in simulation details. Comparison of Kir6.2 and KcsA suggests some degree of flexibility in the filter, thus complicating models of ion selectivity based upon a rigid filter.
- Li-Smerin Y, Hackos DH, Swartz KJ
- A localized interaction surface for voltage-sensing domains on the pore domain of a K+ channel.
- Neuron. 2000; 25: 411-23
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Voltage-gated K+ channels contain a central pore domain and four surrounding voltage-sensing domains. How and where changes in the structure of the voltage-sensing domains couple to the pore domain so as to gate ion conduction is not understood. The crystal structure of KcsA, a bacterial K+ channel homologous to the pore domain of voltage-gated K+ channels, provides a starting point for addressing this question. Guided by this structure, we used tryptophan-scanning mutagenesis on the transmembrane shell of the pore domain in the Shaker voltage-gated K+ channel to localize potential protein-protein and protein-lipid interfaces. Some mutants cause only minor changes in gating and when mapped onto the KcsA structure cluster away from the interface between pore domain subunits. In contrast, mutants producing large changes in gating tend to cluster near this interface. These results imply that voltage-sensing domains interact with localized regions near the interface between adjacent pore domain subunits.
- Zerangue N, Jan YN, Jan LY
- An artificial tetramerization domain restores efficient assembly of functional Shaker channels lacking T1.
- Proc Natl Acad Sci U S A. 2000; 97: 3591-5
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One feature shared by all Shaker-type voltage-gated K(+) channels is a highly conserved domain (T1) located in the cytoplasmic N terminus. The T1 domain is a key determinant of which subtypes can form heteromultimeric channels, suggesting that T1 functions during channel assembly. To better define the role of T1 during channel assembly and separate this function from potential contributions to channel permeation and gating, we replaced the T1 domain (residues 96-183) of ShakerB with a coiled-coil sequence (GCN4-LI) that forms parallel tetramers. Deleting T1 dramatically, but not completely, abolished channel formation under most expression conditions. Channels lacking T1 are functional and K(+)-selective, although they activate at more hyperpolarized membrane potentials and inactivate less completely. Insertion of the artificial tetramerization domain (GCN4-LI) restored efficient channel formation, suggesting that tetramerization of the cytoplasmic T1 domain promotes transmembrane channel assembly by increasing the effective local subunit concentration for T1 compatible subunits. We propose that T1 tetramerization promotes subfamily-specific assembly through kinetic partitioning of the assembly process, but is not required for subsequent steps in channel assembly and folding.
- Bixby KA et al.
- Zn2+-binding and molecular determinants of tetramerization in voltage-gated K+ channels.
- Nat Struct Biol. 1999; 6: 38-43
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The N-terminal, cytoplasmic tetramerization domain (T1) of voltage-gated K+ channels encodes molecular determinants for subfamily-specific assembly of alpha-subunits into functional tetrameric channels. Crystal structures of T1 tetramers from Shaw and Shaker subfamilies reveal a common four-layered scaffolding. Within layer 4, on the hypothetical membrane-facing side of the tetramer, the Shaw T1 tetramer contains four zinc ions; each is coordinated by a histidine and two cysteines from one monomer and by one cysteine from an adjacent monomer. The amino acids involved in coordinating the Zn2+ ion occur in a HX5CX20CC sequence motif that is highly conserved among all Shab, Shaw and Shal subfamily members, but is not found in Shaker subfamily members. We demonstrate by coimmunoprecipitation that a few characteristic residues in the subunit interface are crucial for subfamily-specific tetramerization of the T1 domains.
- Minor DL Jr, Masseling SJ, Jan YN, Jan LY
- Transmembrane structure of an inwardly rectifying potassium channel.
- Cell. 1999; 96: 879-91
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Inwardly rectifying potassium channels (K(ir)), comprising four subunits each with two transmembrane domains, M1 and M2, regulate many important physiological processes. We employed a yeast genetic screen to identify functional channels from libraries of K(ir) 2.1 containing mutagenized M1 or M2 domains. Patterns in the allowed sequences indicate that M1 and M2 are helices. Protein-lipid and protein-water interaction surfaces identified by the patterns were verified by sequence minimization experiments. Second-site suppressor analyses of helix packing indicate that the M2 pore-lining inner helices are surrounded by the M1 lipid-facing outer helices, arranged such that the M1 helices participate in subunit-subunit interactions. This arrangement is distinctly different from the structure of a bacterial potassium channel with the same topology and identifies helix-packing residues as hallmark sequences common to all K(ir) superfamily members.
- Gulbis JM, Mann S, MacKinnon R
- Structure of a voltage-dependent K+ channel beta subunit.
- Cell. 1999; 97: 943-52
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The integral membrane subunits of many voltage-dependent potassium channels are associated with an additional protein known as the beta subunit. One function of beta subunits is to modify K+ channel gating. We have determined the structure of the conserved core of mammalian beta subunits by X-ray crystallography at 2.8 A resolution. Like the integral membrane component of K+ channels, beta subunits form a four-fold symmetric structure. Each subunit is an oxidoreductase enzyme complete with a nicotinamide co-factor in its active site. Several structural features of the enzyme active site, including its location with respect to the four-fold axis, imply that it may interact directly or indirectly with the K+ channel's voltage sensor. This structure suggests a mechanism for coupling membrane electrical excitability directly to chemistry of the cell.
- Morais Cabral JH, Lee A, Cohen SL, Chait BT, Li M, Mackinnon R
- Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain.
- Cell. 1998; 95: 649-55
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The HERG voltage-dependent K+ channel plays a role in cardiac electrical excitability, and when defective, it underlies one form of the long QT syndrome. We have determined the crystal structure of the HERG K+ channel N-terminal domain and studied its role as a modifier of gating using electrophysiological methods. The domain is similar in structure to a bacterial light sensor photoactive yellow protein and provides the first three-dimensional model of a eukaryotic PAS domain. Scanning mutagenesis of the domain surface has allowed the identification of a hydrophobic "hot spot" forming a putative interface with the body of the K+ channel to which it tightly binds. The presence of the domain attached to the channel slows the rate of deactivation. Given the roles of PAS domains in biology, we propose that the HERG N-terminal domain has a regulatory function.
- Goldstein SA, Wang KW, Ilan N, Pausch MH
- Sequence and function of the two P domain potassium channels: implications of an emerging superfamily.
- J Mol Med. 1998; 76: 13-20
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A new superfamily of K+ channels has emerged in the past 2 years. Notable for possessing two pore-forming P domains in each subunit, members of the superfamily have been recognized through phylogeny from micro-organisms to humans. Four subfamilies of two P domain channels have been isolated thus far; among these are the first cloned examples of outward rectifier and open rectifier (or leak) K+ channels. The two P domain K+ channels offer a new perspective from which to glimpse the molecular basis for function and dysfunction of K+-selective ion channels.
- Moczydlowski E
- Chemical basis for alkali cation selectivity in potassium-channel proteins.
- Chem Biol. 1998; 5: 291301-291301
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The determination of the crystal structure of a K+-selective channel protein from Streptomyces lividans reveals how the rapid movement of K+ across membranes is catalyzed by a large family of pore-forming proteins. Many features of the structure mirror hypotheses, predictions and models of K+ channels developed over the past four decades of functional analysis.
- Edwards G, Weston AH
- Recent advances in potassium channel modulation.
- Prog Drug Res. 1997; 49: 93-121
- Ludwig J, Owen D, Pongs O
- Carboxy-terminal domain mediates assembly of the voltage-gated rat ether-a-go-go potassium channel.
- EMBO J. 1997; 16: 6337-45
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The specific assembly of subunits to oligomers is an important prerequisite for producing functional potassium channels. We have studied the assembly of voltage-gated rat ether-a-go-go (r-eag) potassium channels with two complementary assays. In protein overlay binding experiments it was shown that a 41-amino-acid domain, close to the r-eag subunit carboxy-terminus, is important for r-eag subunit interaction. In an in vitro expression system it was demonstrated that r-eag subunits lacking this assembly domain cannot form functional potassium channels. Also, a approximately 10-fold molar excess of the r-eag carboxy-terminus inhibited in co-expression experiments the formation of functional r-eag channels. When the r-eag carboxy-terminal assembly domain had been mutated, the dominant-negative effect of the r-eag carboxy-terminus on r-eag channel expression was abolished. The results demonstrate that a carboxy-terminal assembly domain is essential for functional r-eag potassium channel expression, in contrast to the one of Shaker-related potassium channels, which is directed by an amino-terminal assembly domain.
- Albagli O, Dhordain P, Deweindt C, Lecocq G, Leprince D
- The BTB/POZ domain: a new protein-protein interaction motif common to DNA- and actin-binding proteins.
- Cell Growth Differ. 1995; 6: 1193-8
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The BTB/POZ domain defines a newly characterized protein-protein interaction interface. It is highly conserved throughout metazoan evolution and generally found at the NH2 terminus of either actin-binding or, more commonly, nuclear DNA-binding proteins. By mediating protein binding in large aggregates, the BTB/POZ domain serves to organize higher order macromolecular complexes involved in ring canal formation or chromatin folding.
- Suzuki M
- [A pH-sensitive K+ channel]
- Tanpakushitsu Kakusan Koso. 1995; 40: 2307-10
- Shen NV, Pfaffinger PJ
- Molecular recognition and assembly sequences involved in the subfamily-specific assembly of voltage-gated K+ channel subunit proteins.
- Neuron. 1995; 14: 625-33
- Display abstract
We are analyzing features of the K+ channel subunit proteins that are critical for function and regulation of these proteins. Our studies show biochemically that subunit proteins from the Shaker and Shaw subfamilies fail to assemble into a heteromultimer. The basis for this incompatibility is the sequences contained within the T1 assembly domain. For a subunit protein to heteromultimerize with a Shaker subunit protein, two regions within the T1 domain, A and B, must be of the Shaker subtype. Finally, we show that the incompatibility of a Shaw A region for assembly with a Shaker protein depends upon the composition of a 30 amino acid conserved sequence in the A region.
- Kerr ID, Sansom MS
- Sequence analysis and molecular dynamics studies of potassium channel transmembrane helices.
- Biochem Soc Trans. 1995; 23: 415-415
- Timpe LC, Peller L
- A random flight chain model for the tether of the Shaker K+ channel inactivation domain.
- Biophys J. 1995; 69: 2415-8
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Rapid inactivation of Shaker K+ channels occurs when a domain in the amino terminal region of the channel protein blocks the pore. Some part of the sequence between the inactivating domain and the first transmembrane segment may form a flexible tether. We consider the possibility that the tether has no secondary structure, but is rather a polypeptide random coil. The local concentration of the tethered inactivation domain and the dependence of the inactivation rate on chain length can then be calculated by using the Jacobson-Stockmayer equation. A chain of 30-100 amino acids is consistent with the sensitivity of the inactivation rate to chain length mutations.
- Tytgat J
- Mutations in the P-region of a mammalian potassium channel (RCK1): a comparison with the Shaker potassium channel.
- Biochem Biophys Res Commun. 1994; 203: 513-8
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Deletion mutants of Shaker K channels lacking the middlemost 2 residues of the amino acid sequence GYGD in their P-region lose K-selectivity and become functionally similar to voltage-activated Ca channels. Ca channel characteristics are also conferred on voltage-activated Na channels when residues K in domain III and/or A in domain IV in the P-region of the Na channel are replaced by E residues. In this study, we have investigated a possible evolutionary connection between voltage-activated K and Na channels. Mutant monomeric and multi-heteromeric RCK1 K channel cDNAs were made to match the residues at equivalent positions in the P-region of the Na channel. We found that in contrast to mutant Shaker K channels, the same mutants in RCK1 K channels did not yield functional expression. Therefore possible Na channel-like ion conduction properties conferred on K channels could not be demonstrated. However, our results show that the same mutations in highly homologous channels can produce different effects and point to hitherto unknown structural differences in the P-region of these homologous K channels. Therefore we conclude that extrapolation of the structural and functional importance of residues should be done with caution, even when ion channels belong to the same family.
- Brown AM et al.
- The potassium pore and its regulation.
- Ann N Y Acad Sci. 1993; 707: 74-80
