Summary: K-Cl Co-transporter type 1 (KCC1)

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Wikipedia: Electroneutral cation-Cl
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Electroneutral cation-Cl Edit Wikipedia article

K-Cl Co-transporter type 1 (KCC1)

Identifiers

Symbol

KCl_Cotrans_1

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe
PDBsum	structure summary

In molecular biology, the electroneutral cation-Cl (electroneutral potassium-chloride cotransporter) family of proteins are a family of solute carrier proteins. This family includes the products of the Human genes: SLC12A1, SLC12A1, SLC12A2, SLC12A3, SLC12A4, SLC12A5, SLC12A6, SLC12A7, SLC12A8 and SLC12A9.

The K-Cl co-transporter (KCC) mediates the coupled movement of K⁺ and Cl^- ions across the plasma membrane of many animal cells. This transport is involved in the regulatory volume decrease in response to cell swelling in red blood cells, and has been proposed to play a role in the vectorial movement of Cl^- across kidney epithelia. The transport process involves one for one electroneutral movement of K⁺ together with Cl^-, and, in all known mammalian cells, the net movement is outward.^[1]

The neuronal KCC subtype KCC2 is cell-volume insensitive and plays a unique role in maintaining low intracellular Cl^-concentration, which is required in neurones for the functioning of Cl^- dependent fast synaptic inhibition, mediated by certain neurotransmitters, such as gamma-aminobutyric acid (GABA) and glycine.

Three isoforms of the K-Cl co-transporter have been described, termed KCC1 (SLC12A4), KCC2 (SLC12A5), and KCC3 (SLC12A6), containing 1085, 1116 and 1150 amino acids, respectively. They are predicted to have 12 transmembrane (TM) regions in a central hydrophobic domain, together with hydrophilic N- and C-termini that are likely cytoplasmic. Comparison of their sequences with those of other ion-transporting membrane proteins reveals that they are part of a new superfamily of cation-chloride co-transporters, which includes the Na-Cl and Na-K-2Cl co-transporters. KCC1 and KCC3 are widely expressed in human tissues, while KCC2 is expressed only in brain neurones, making it likely that this is the isoform responsible for maintaining low Cl^- concentration in neurones.^[2]^[3]^[4]

KCC1 is widely expressed in human tissues, and when heterologously expressed, possesses the functional characteristics of the well-studied red blood cell K-Cl co-transporter, including stimulation by both swelling and N-ethylmaleimide. Several splice variants have also been identified.

KCC3 is widely expressed in human tissues and, like KCC1, is stimulated by both swelling and N-ethylmaleimide. The induction of KCC3 is up-regulated by vascular endothelial growth factor and down-regulated by tumour necrosis factor. Defects in KCC3 are linked to agenesis of the corpus callosum with peripheral neuropathy.^[5] This disorder is characterised by severe progressive sensorimotor neuropathy, mental retardation, dysmorphic features and complete or partial agenesis of the corpus callosum.

[edit] References

^ Gillen CM, Brill S, Payne JA, Forbush B (July 1996). "Molecular cloning and functional expression of the K-Cl cotransporter from rabbit, rat, and human. A new member of the cation-chloride cotransporter family". J. Biol. Chem. 271 (27): 16237–44. doi:10.1074/jbc.271.27.16237. PMID 8663127.
^ Payne JA, Stevenson TJ, Donaldson LF (July 1996). "Molecular characterization of a putative K-Cl cotransporter in rat brain. A neuronal-specific isoform". J. Biol. Chem. 271 (27): 16245–52. PMID 8663311.
^ Rivera C, Voipio J, Payne JA, Ruusuvuori E, Lahtinen H, Lamsa K, Pirvola U, Saarma M, Kaila K (January 1999). "The K+/Cl- co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation". Nature 397 (6716): 251–5. doi:10.1038/16697. PMID 9930699.
^ Race JE, Makhlouf FN, Logue PJ, Wilson FH, Dunham PB, Holtzman EJ (December 1999). "Molecular cloning and functional characterization of KCC3, a new K-Cl cotransporter". Am. J. Physiol. 277 (6 Pt 1): C1210-9. PMID 10600773.
^ Howard HC, Mount DB, Rochefort D, Byun N, Dupre N, Lu J, Fan X, Song L, Riviere JB, Prevost C, Horst J, Simonati A, Lemcke B, Welch R, England R, Zhan FQ, Mercado A, Siesser WB, George AL, McDonald MP, Bouchard JP, Mathieu J, Delpire E, Rouleau GA (November 2002). "The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum". Nat. Genet. 32 (3): 384–92. doi:10.1038/ng1002. PMID 12368912.

This article incorporates text from the public domain Pfam and InterPro IPR018491

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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K-Cl Co-transporter type 1 (KCC1) Provide feedback

No Pfam abstract.

External database links

PANDIT:	PF03522
Pseudofam:	PF03522
SYSTERS:	KCl_Cotrans_1
Transporter classification:	2.A.30

This tab holds annotation information from the InterPro database.

InterPro entry IPR018491

The K-Cl co-transporter (KCC) mediates the coupled movement of K⁺ and Cl^- ions across the plasma membrane of many animal cells. This transport is involved in the regulatory volume decrease in response to cell swelling in red blood cells, and has been proposed to play a role in the vectorial movement of Cl^- across kidney epithelia. The transport process involves one for one electroneutral movement of K⁺ together with Cl^-, and, in all known mammalian cells, the net movement is outward [PUBMED:8663127].

In neurones, it appears to play a unique role in maintaining low intracellular Cl^-concentration, which is required for the functioning of Cl^- dependent fast synaptic inhibition, mediated by certain neurotransmitters, such as gamma-aminobutyric acid (GABA) and glycine.

Three isoforms of the K-Cl co-transporter have been described, termed KCC1 KCC2, and KCC3, containing 1085, 1116 and 1150 amino acids, respectively. They are predicted to have 12 transmembrane (TM) regions in a central hydrophobic domain, together with hydrophilic N- and C-termini that are likely cytoplasmic. Comparison of their sequences with those of other ion-tranporting membrane proteins reveals that they are part of a new superfamily of cation-chloride co-transporters, which includes the Na-Cl and Na-K-2Cl co-transporters. KCC1 and KCC3 are widely expressed in human tissues, while KCC2 is are expressed only in brain neurones, making it likely that this is the isoform responsible for maintaining low Cl^- concentration in neurones [PUBMED:8663311, PUBMED:9930699, PUBMED:10600773].

KCC1 is widely expressed in human tissues, and when heterologously expressed, possesses the functional characteristics of the well-studied red blood cell K-Cl co-transporter, including stimulation by both swelling and N-ethylmaleimide. Several splice variants have also been identified.

KCC3 is widely expressed in human tissues and, like KCC1, is stimulated by both swelling and N-ethylmaleimide. The induction of KCC3 is up-regulated by vascular endothelial growth factor and down-regulated by tumour necrosis factor. Defects in KCC3 are linked to agenesis of the corpus callosum with peripheral neuropathy [PUBMED:12368912]. This disorder is characterised by severe progressive sensorimotor neuropathy, mental retardation, dysmorphic features and complete or partial agenesis of the corpus callosum.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Cellular component	membrane (GO:0016020)
Molecular function	transporter activity (GO:0005215)
Biological process	ion transport (GO:0006811)

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.

Alignment types

We make a range of alignments for each Pfam-A family:

seed: the curated alignment from which the HMM for the family is built
full: the alignment generated by searching the sequence database using the HMM
RP15/RP35/RP55/RP75: Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
NCBI: alignment generated by searching the NCBI sequence database using the family HMM
meta: alignment generated by searching the metagenomics sequence database using the family HMM

Viewing

You can see the alignments as HTML or in three different sequence viewers:

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HTML: an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
PP/Heatmap: an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
Pfam viewer: an HTML-based viewer that uses DAS to retrieve alignment fragments on request

Reformatting

You can download (or view in your browser) a text representation of a Pfam alignment in various formats:

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You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.

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You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

	Seed (3)	Full (128)	Representative proteomes				NCBI (150)	Meta (0)
	Seed (3)	Full (128)	RP15 (2)	RP35 (5)	RP55 (18)	RP75 (48)	NCBI (150)	Meta (0)
Jalview	View	View	View	View	View	View	View
HTML	View	View	View	View	View	View
PP/heatmap	₁	View	View	View	View	View
Pfam viewer	View	View

¹Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: available, not generated, — not available.

Format an alignment

	Seed (3)	Full (128)	Representative proteomes				NCBI (150)	Meta (0)
	Seed (3)	Full (128)	RP15 (2)	RP35 (5)	RP55 (18)	RP75 (48)	NCBI (150)	Meta (0)
Alignment:
Format:
Order:	Tree Alphabetical
Sequence:	Inserts lower case All upper case
Gaps:
Download/view:	Download View

Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

	Seed (3)	Full (128)	Representative proteomes				NCBI (150)	Meta (0)
	Seed (3)	Full (128)	RP15 (2)	RP35 (5)	RP55 (18)	RP75 (48)	NCBI (150)	Meta (0)
Raw Stockholm	Download	Download	Download	Download	Download	Download	Download
Gzipped	Download	Download	Download	Download	Download	Download	Download

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation

Seed source:

PRINTS

Previous IDs:

none

Type:

Family

Author:

Griffiths-Jones SR

Number in seed:

3

Number in full:

128

Average length of the domain:

29.80 aa

Average identity of full alignment:

66 %

Average coverage of the sequence by the domain:

2.91 %

HMM information

HMM build commands:

build method: hmmbuild -o /dev/null HMM SEED

search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	25.0	25.0
Trusted cut-off	28.0	26.8
Noise cut-off	24.5	23.1

Model length:

30

Family (HMM) version:

10

Download:

download the raw HMM for this family

Species distribution

Sunburst
Tree

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.

How the sunburst is generated

The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.

In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:

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kingdom
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order
family
genus
species

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Anomalies in the taxonomy tree

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Missing taxonomic levels

Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.

Unmapped species names

The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.

So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".

Sub-species

Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.

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For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.

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Species trees

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Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.

If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.

Interactive tree

For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.

We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.

Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.

We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.

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Archea	Eukaryota
Bacteria	Other sequences
Viruses	Unclassified
Viroids	Unclassified sequence

Family: KCl_Cotrans_1 (PF03522)

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