Potassium channel tetramerisation domain

Pfam_box
Symbol = K_tetra
Name = K+ channel tetramerisation domain


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caption =
Pfam= PF02214
InterPro= IPR003131
SMART=
Prosite =
SCOP = 1t1d
TCDB =
OPM family= 8
OPM protein= 2a79
PDB=PDB3|3kvtS:12-102 PDB3|1nn7A:43-132 PDB3|1s1gB:42-131PDB3|1dsxG:35-119 PDB3|1qdvB:35-126 PDB3|1qdwH:35-119PDB3|2a79B:35-126 PDB3|1exbE:39-129 PDB3|1a68 :68-152PDB3|1eofA:68-159 PDB3|1eodA:68-159 PDB3|1eoeA:68-159PDB3|1t1dA:68-159 K+ channel tetramerisation domain is the N-terminal, cytoplasmic tetramerisation domain (T1) of voltage-gated K+ channels. It defines molecular determinants for subfamily-specific assembly of alpha-subunits into functional tetrameric channels [1] . It is distantly related to the BTB/POZ domain Pfam|PF00651.

Potassium channels

Potassium channels are the most diverse group of the ion channel familycite journal |author=Perney TM, Kaczmarek LK |title=The molecular biology of K+ channels |journal=Curr. Opin. Cell Biol. |volume=3 |issue=4 |pages=663–670 |year=1991 |pmid=1772658 |doi=10.1016/0955-0674(91)90039-2] cite journal |author=Williams JB, Luneau C, Smith JS, Wiedmann R |title=Shaw-like rat brain potassium channel cDNA's with divergent 3' ends |journal=FEBS Lett. |volume=288 |issue=1 |pages=163–167 |year=1991 |pmid=1879548 |doi=10.1016/0014-5793(91)81026-5] . They are important in shaping the action potential, and in neuronal excitability and plasticitycite journal |author=Jan LY, Jan YN, Tempel BL |title=Cloning of a probable potassium channel gene from mouse brain |journal=Nature |volume=332
issue=6167 |pages=837–839 |year=1988 |pmid=2451788 |doi=10.1038/332837a0] . The potassium channel family is composed of several functionally distinct isoforms, which can be broadly separated into 2 groupscite journal |author=Stuhmer W, Ruppersberg JP, Schroter KH, Sakmann B, Stocker M, Giese KP, Perschke A, Baumann A, Pongs O |title=Molecular basis of functional diversity of voltage-gated potassium channels in mammalian brain |journal=EMBO J. |volume=8 |issue=11 |pages=3235–3244 |year=1989 |pmid=2555158] : the practically non-inactivating 'delayed' group and the rapidly inactivating 'transient' group.

These are all highly similar proteins, with only small amino acid changes causing the diversity of the voltage-dependent gating mechanism, channel conductance and toxin binding properties. Each type of K⁺ channel is activated by different signals and conditions depending on their type of regulation: some open in response to depolarisation of the plasma membrane; others in response to hyperpolarisation or an increase in intracellular calcium concentration; some can be regulated by binding of a transmitter, together with intracellular kinases; while others are regulated by GTP-binding proteins or other second messengerscite journal |author=Jan LY, Jan YN, Schwarz TL, Tempel BL, Papazian DM |title=Multiple potassium-channel components are produced by alternative splicing at the Shaker locus in Drosophila |journal=Nature |volume=331 |issue=6152 |pages=137–142 |year=1988 |pmid=2448635 |doi=10.1038/331137a0] . In eukaryotic cells, K⁺ channels are involved in neural signalling and generation ofthe cardiac rhythm, act as effectors in signal transduction pathways involving G protein-coupled receptors (GPCRs)and may have a role in target cell lysis by cytotoxic T-lymphocytescite journal |author=Mattei MG, Lesage F, Lazdunski M, Romey G, Barhanin J, Attali B, Honore E, Ricard P, Schmid-Alliana A |title=Cloning, functional expression, and regulation of two K+ channels in human T lymphocytes |journal=J. Biol. Chem. |volume=267 |issue=12 |pages=8650–8657 |year=1992 |pmid=1373731] . In prokaryotic cells, they play a role in the maintenance of ionic homeostasiscite journal |author=Miller C |title=An overview of the potassium channel family |journal=Genome Biol. |volume=1 |issue=4 |pages=- |year=2000 |pmid=11178249 |doi=10.1186/gb-2000-1-4-reviews0004] .

Alpha subunits of the channels

All K⁺ channels discovered so far possess a core of alpha subunits, each comprising either one or two copies of a highly conserved pore loop domain (P-domain). The P-domain contains the sequence (T/SxxTxGxG), which hasbeen termed the K⁺ selectivity sequence. In families that contain one P-domain, four subunits assemble to form a selective pathway for K⁺ across the membrane. However, it remains unclear how the 2 P-domain subunits assemble to form a selective pore. The functional diversity of these families can arise through homo- or hetero-associations of alpha subunits or association with auxiliary cytoplasmic beta subunits. K⁺ channel subunits containing one pore domain can be assigned into one of two superfamilies: those that possess six transmembrane (TM) domains and those that possess only two TM domains. The six TM domain superfamily can be further subdivided into conserved gene families: the voltage-gated (Kv) channels; the KCNQ channels (originally known as KvLQT channels); the EAG-like K⁺ channels; and three types of calcium (Ca)-activated K⁺ channels (BK, IK and SK)cite journal |author=Ashcroft FM |title=Voltage-gated K+ channels |journal= |volume= |issue= |pages=97–123 |year=2000] . The 2TM domain family comprises inward-rectifying K⁺ channels. In addition, there are K⁺ channel alpha-subunits that possess two P-domains. These are usually highly regulated K⁺ selective leak channels.

The Kv family can be divided into several subfamilies on the basis of sequence similarity and function. Four of these subfamilies, Kv1 (Shaker), Kv2 (Shab), Kv3 (Shaw) and Kv4 (Shal), consist of pore-forming alpha subunits that associate with different types of beta subunit. Each alpha subunit comprises six hydrophobic TM domains with a P-domain between the fifth and sixth, which partially resides in the membrane. The fourth TM domain has positively charged residues at every third residue and acts as a voltage sensor, which triggers the conformational change that opens the channel pore in response to a displacement in membrane potentialcite journal |author=Sansom MS |title=Potassium channels: watching a voltage-sensor tilt and twist |journal=Curr. Biol. |volume=10 |issue=5 |pages=- |year=2000 |pmid=10712896 |doi=10.1016/S0960-9822(00)00354-7] . More recently, 4 new electrically-silent alpha subunits have beencloned: Kv5 (KCNF), Kv6 (KCNG), Kv8 and Kv9 (KCNS). These subunits do not themselves possess any functional activity, but appear to form heteromeric channels with Kv2 subunits, and thus modulate Shab channel activitycite journal |author=Duprat F, Lazdunski M, Heurteaux C, Salinas M, Hugnot JP |title=New modulatory alpha subunits for mammalian Shab K+ channels |journal=J. Biol. Chem. |volume=272 |issue=39 |pages=24371–24379 |year=1997 |pmid=9305895 |doi=10.1074/jbc.272.39.24371] . When highly expressed, they inhibit channel activity, but at lower levels show more specific modulatory actions.

Tetramerization domain

The N-terminal, cytoplasmic tetramerization domain (T1) of voltage-gated potassium channels encodes molecular determinants for subfamily-specific assembly of alpha-subunits into functional tetrameric channelscite journal |author=Kreusch A, Choe S, Bixby KA, Nanao MH, Shen NV, Bellamy H, Pfaffinger PJ |title=Zn2+-binding and molecular determinants of tetramerization in voltage-gated K+ channels |journal=Nat. Struct. Biol. |volume=6 |issue=1 |pages=38–43 |year=1999 |pmid=9886290 |doi=10.1038/4911] . This domain is found in a subset of a larger group of proteins that contain the BTB/POZ domain.

Human proteins containing this domain

BTBD10; KCNA1; KCNA10; KCNA2; KCNA3; KCNA4; KCNA5; KCNA6;
KCNA7; KCNB1; KCNB2; KCNC1; KCNC2; KCNC3; KCNC4; KCND1;
KCND2; KCND3; KCNF1; KCNG1; KCNG2; KCNG3; KCNG4; KCNRG;
KCNS1; KCNS2; KCNS3; KCNV1; KCNV2; KCTD1; KCTD10; KCTD11;
KCTD12; KCTD13; KCTD14; KCTD15; KCTD16; KCTD17; KCTD18; KCTD19;
KCTD2; KCTD20; KCTD21; KCTD3; KCTD4; KCTD5; KCTD6; KCTD7;
KCTD8; KCTD9; SHKBP1; TNFAIP1;

References

Further reading

*Zn2+-binding and molecular determinants of tetramerization in voltage-gated K+ channels. Bixby KA, Nanao MH, Shen NV, Kreusch A, Bellamy H, Pfaffinger PJ, Choe S; Nat Struct Biol 1999;6:38-43. PMID|9886290