P51801 (CLCKB_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Chloride channel protein ClC-Kb
Short name=Chloride channel Kb

Alternative name(s):
ClC-K2

Gene names

Name:

CLCNKB

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	687 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Voltage-gated chloride channel. Chloride channels have several functions including the regulation of cell volume; membrane potential stabilization, signal transduction and transepithelial transport. May be important in urinary concentrating mechanisms. Ref.6
Subunit structure	Interacts with BSND. Forms heteromers with BSND in the thick ascending limb of Henle and more distal segments By similarity.
Subcellular location	Cell membrane; Multi-pass membrane protein.
Tissue specificity	Expressed predominantly in the kidney. Ref.6
Involvement in disease	Bartter syndrome 3 (BS3) [MIM:607364]: An autosomal recessive disorder characterized by impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and varying degrees of hypercalciuria. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.9 Bartter syndrome 4B (BS4B) [MIM:613090]: A digenic, recessive disorder characterized by impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and varying degrees of hypercalciuria. Bartter syndrome type 4B is associated with sensorineural deafness. Note: The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. Loss-of-function of both CLCNKA and CLCNKB results in the disease phenotype (Ref.8). Ref.7 Ref.8
Miscellaneous	Compared with CLCNKA/BSND, CLCNKB/BSND is more sensitive to pH and less responsive to Ca2+.
Sequence similarities	Belongs to the chloride channel (TC 2.A.49) family. CLCNKB subfamily. [View classification] Contains 2 CBS domains.

Ontologies

Keywords
Biological process	Ion transport Transport
Cellular component	Cell membrane Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Bartter syndrome Deafness Disease mutation
Domain	CBS domain Repeat Transmembrane Transmembrane helix
Ligand	Chloride
Molecular function	Chloride channel Ion channel Voltage-gated channel
PTM	Glycoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	excretion Traceable author statement Ref.9. Source: ProtInc
Cellular_component	chloride channel complex Inferred from electronic annotation. Source: UniProtKB-KW integral to plasma membrane Traceable author statement Ref.1. Source: ProtInc
Molecular_function	voltage-gated chloride channel activity Traceable author statement Ref.1. Source: ProtInc
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P51801-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P51801-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-49: MEEFVGLREG...KQKLFRLGED → MPCPPLLSVP...RAHLRSVSPP
     50-218: Missing.
     616-616: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 687	687	Chloride channel protein ClC-Kb		PRO_0000094459
Regions
	Topological domain	1 – 50	50	Cytoplasmic Potential
	Transmembrane	51 – 71	21	Helical; Potential
	Transmembrane	94 – 114	21	Helical; Potential
	Transmembrane	161 – 181	21	Helical; Potential
	Transmembrane	202 – 222	21	Helical; Potential
	Transmembrane	236 – 256	21	Helical; Potential
	Transmembrane	282 – 302	21	Helical; Potential
	Transmembrane	325 – 345	21	Helical; Potential
	Transmembrane	396 – 416	21	Helical; Potential
	Transmembrane	417 – 437	21	Helical; Potential
	Transmembrane	452 – 472	21	Helical; Potential
	Transmembrane	486 – 506	21	Helical; Potential
	Domain	551 – 609	59	CBS 1
	Domain	626 – 684	59	CBS 2
Amino acid modifications
	Glycosylation	679	1	N-linked (GlcNAc...) Potential
Natural variations
	Alternative sequence	1 – 49	49	MEEFV…RLGED → MPCPPLLSVPVRAAGEQDRW VREEVTWGGGPTVTGGWGWR AHLRSVSPP in isoform 2.		VSP_045965
	Alternative sequence	50 – 218	169	Missing in isoform 2.		VSP_045966
	Alternative sequence	616	1	Missing in isoform 2.		VSP_045967
	Natural variant	4	1	F → L. Corresponds to variant rs34851419 [ dbSNP | Ensembl ].		VAR_033770
	Natural variant	27	1	R → L. Ref.1 Ref.2 Corresponds to variant rs2015352 [ dbSNP | Ensembl ].		VAR_046797
	Natural variant	88	1	S → R. Corresponds to variant rs5256 [ dbSNP | Ensembl ].		VAR_014466
	Natural variant	104	1	V → I. Corresponds to variant rs35530360 [ dbSNP | Ensembl ].		VAR_033771
	Natural variant	124	1	P → L in BS3. Ref.9		VAR_001624
	Natural variant	126	1	V → L. Corresponds to variant rs5258 [ dbSNP | Ensembl ].		VAR_046798
	Natural variant	143	1	N → H. Corresponds to variant rs5259 [ dbSNP | Ensembl ].		VAR_014467
	Natural variant	204	1	A → T in BS3. Ref.9		VAR_001625
	Natural variant	214	1	A → G. Ref.1 Ref.2 Corresponds to variant rs1889789 [ dbSNP | Ensembl ].		VAR_033772
	Natural variant	287	1	A → V. Ref.1 Ref.2 Ref.3 Corresponds to variant rs34188929 [ dbSNP | Ensembl ].		VAR_069104
	Natural variant	334	1	V → L. Corresponds to variant rs5251 [ dbSNP | Ensembl ].		VAR_014468
	Natural variant	349	1	A → D in BS3. Ref.9		VAR_001626
	Natural variant	395	1	R → W. Corresponds to variant rs34255952 [ dbSNP | Ensembl ].		VAR_046799
	Natural variant	419	1	I → V. Corresponds to variant rs6650119 [ dbSNP | Ensembl ].		VAR_033773
	Natural variant	432	1	Y → H in BS3. Ref.9		VAR_001627
	Natural variant	438	1	R → C in BS3. Ref.9		VAR_001628
	Natural variant	481	1	T → S. Corresponds to variant rs12140311 [ dbSNP | Ensembl ].		VAR_046800
	Natural variant	562	1	M → T. Ref.1 Ref.2 Corresponds to variant rs5253 [ dbSNP | Ensembl ].		VAR_014469
	Natural variant	578	1	K → E. Ref.1 Ref.2 Corresponds to variant rs2275166 [ dbSNP | Ensembl ].		VAR_024409
	Natural variant	660	1	S → L. Corresponds to variant rs5255 [ dbSNP | Ensembl ].		VAR_046801
Experimental info
	Sequence conflict	609	1	S → P in BAG53595. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified February 9, 2010. Version 3. Checksum: 4D28BC19DDD5D412	FASTA	687	75,446
	10 20 30 40 50 60 MEEFVGLREG SSGNPVTLQE LWGPCPRIRR GIRGGLEWLK QKLFRLGEDW YFLMTLGVLM 70 80 90 100 110 120 ALVSCAMDLA VESVVRAHQW LYREIGDSHL LRYLSWTVYP VALVSFSSGF SQSITPSSGG 130 140 150 160 170 180 SGIPEVKTML AGVVLEDYLD IKNFGAKVVG LSCTLACGST LFLGKVGPFV HLSVMMAAYL 190 200 210 220 230 240 GRVRTTTIGE PENKSKQNEM LVAAAAVGVA TVFAAPFSGV LFSIEVMSSH FSVWDYWRGF 250 260 270 280 290 300 FAATCGAFMF RLLAVFNSEQ ETITSLYKTS FRVDVPFDLP EIFFFVALGG LCGILGSAYL 310 320 330 340 350 360 FCQRIFFGFI RNNRFSSKLL ATSKPVYSAL ATLVLASITY PPSAGRFLAS RLSMKQHLDS 370 380 390 400 410 420 LFDNHSWALM TQNSSPPWPE ELDPQHLWWE WYHPRFTIFG TLAFFLVMKF WMLILATTIP 430 440 450 460 470 480 MPAGYFMPIF VYGAAIGRLF GETLSFIFPE GIVAGGITNP IMPGGYALAG AAAFSGAVTH 490 500 510 520 530 540 TISTALLAFE VTGQIVHALP VLMAVLAANA IAQSCQPSFY DGTVIVKKLP YLPRILGRNI 550 560 570 580 590 600 GSHRVRVEHF MNHSITTLAK DMPLEEVVKV VTSTDVAKYP LVESTESQIL VGIVRRAQLV 610 620 630 640 650 660 QALKAEPPSW APGHQQCLQD ILAAGCPTEP VTLKLSPETS LHEAHNLFEL LNLHSLFVTS 670 680 RGRAVGCVSW VEMKKAISNL TNPPAPK
	Isoform 2 [UniParc]. Checksum: C2F9D66B22BBD4B1	FASTA	517	56,998
	10 20 30 40 50 60 MPCPPLLSVP VRAAGEQDRW VREEVTWGGG PTVTGGWGWR AHLRSVSPPG VLFSIEVMSS 70 80 90 100 110 120 HFSVWDYWRG FFAATCGAFM FRLLAVFNSE QETITSLYKT SFRVDVPFDL PEIFFFVALG 130 140 150 160 170 180 GLCGILGSAY LFCQRIFFGF IRNNRFSSKL LATSKPVYSA LATLVLASIT YPPSAGRFLA 190 200 210 220 230 240 SRLSMKQHLD SLFDNHSWAL MTQNSSPPWP EELDPQHLWW EWYHPRFTIF GTLAFFLVMK 250 260 270 280 290 300 FWMLILATTI PMPAGYFMPI FVYGAAIGRL FGETLSFIFP EGIVAGGITN PIMPGGYALA 310 320 330 340 350 360 GAAAFSGAVT HTISTALLAF EVTGQIVHAL PVLMAVLAAN AIAQSCQPSF YDGTVIVKKL 370 380 390 400 410 420 PYLPRILGRN IGSHRVRVEH FMNHSITTLA KDMPLEEVVK VVTSTDVAKY PLVESTESQI 430 440 450 460 470 480 LVGIVRRAQL VQALKAEPPS WAPGHQCLQD ILAAGCPTEP VTLKLSPETS LHEAHNLFEL 490 500 510 LNLHSLFVTS RGRAVGCVSW VEMKKAISNL TNPPAPK

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Two highly homologous members of the ClC chloride channel family in both rat and human kidney." Kieferle S., Fong P., Bens M., Vandewalle A., Jentsch T. Proc. Natl. Acad. Sci. U.S.A. 91:6943-6947(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANTS LEU-27; GLY-214; VAL-287; THR-562 AND GLU-578. Tissue: Kidney.
[2]	"Cloning, tissue distribution, and intrarenal localization of ClC chloride channels in human kidney." Takeuchi Y., Uchida S., Marumo F., Sasaki S. Kidney Int. 48:1497-1503(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANTS LEU-27; GLY-214; VAL-287; THR-562 AND GLU-578. Tissue: Kidney.
[3]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), VARIANT VAL-287. Tissue: Uterus.
[4]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"Refined chromosomal localization of six human CLCN chloride ion channel genes." Schutte B.C., Malik M.I., Fingert J., Barna T.J., Stone E., Lamb F.S. Submitted (MAR-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 153-203.
[6]	"Barttin is a Cl- channel beta-subunit crucial for renal Cl-reabsorption and inner ear K+ secretion." Estevez R., Boettger T., Stein V., Birkenhaeger R., Otto E., Hildebrandt F., Jentsch T.J. Nature 414:558-561(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTIONAL CHARACTERIZATION, TISSUE SPECIFICITY.
[7]	"Salt wasting and deafness resulting from mutations in two chloride channels." Schlingmann K.P., Konrad M., Jeck N., Waldegger P., Reinalter S.C., Holder M., Seyberth H.W., Waldegger S. N. Engl. J. Med. 350:1314-1319(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN BS4B.
[8]	"Molecular analysis of digenic inheritance in Bartter syndrome with sensorineural deafness." Nozu K., Inagaki T., Fu X.J., Nozu Y., Kaito H., Kanda K., Sekine T., Igarashi T., Nakanishi K., Yoshikawa N., Iijima K., Matsuo M. J. Med. Genet. 45:182-186(2008) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN BS4B.
[9]	"Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III." Simon D.B., Bindra R.S., Mansfield T.A., Nelson-Williams C., Mendonca E., Stone R., Schurman S., Nayir A., Alpay H., Bakkaloglu A., Rodriguez-Soriano J., Morales J.M., Sanjad S.A., Taylor C.M., Pilz D., Brem A., Trachtman H., Griswold W. , Richard G.A., John E., Lifton R.P. Nat. Genet. 17:171-178(1997) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS BS3 LEU-124; THR-204; ASP-349; HIS-432 AND CYS-438.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	Z30644 mRNA. Translation: CAA83121.1. S80315 mRNA. Translation: AAB35898.1. AK098217 mRNA. Translation: BAG53595.1. AL355994 Genomic DNA. Translation: CAI16140.1. AL355994 Genomic DNA. Translation: CAI16141.1. U93879 Genomic DNA. Translation: AAB65149.1.
IPI	IPI00020881. IPI00641080.
PIR	D57713.
RefSeq	NP_000076.2. NM_000085.4. NP_001159417.2. NM_001165945.2.
UniGene	Hs.352243.
3D structure databases
ProteinModelPortal	P51801.
SMR	P51801. Positions 542-687.
ModBase	Search...
Protein-protein interaction databases
MINT	MINT-7969230.
STRING	9606.ENSP00000364831.
PTM databases
PhosphoSite	P51801.
Polymorphism databases
DMDM	288558843.
Proteomic databases
PaxDb	P51801.
PRIDE	P51801.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000375667; ENSP00000364819; ENSG00000184908. ENST00000375679; ENSP00000364831; ENSG00000184908.
GeneID	1188.
KEGG	hsa:1188.
UCSC	uc001axx.4. human. uc001axy.4. human.
Organism-specific databases
CTD	1188.
GeneCards	GC01P016370.
H-InvDB	HIX0020336.
HGNC	HGNC:2027. CLCNKB.
MIM	602023. gene. 607364. phenotype. 613090. phenotype.
neXtProt	NX_P51801.
Orphanet	93605. Classic Bartter syndrome. 358. Gitelman syndrome. 89938. Infantile Bartter syndrome with deafness.
PharmGKB	PA26554.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0038.
HOGENOM	HOG000231297.
HOVERGEN	HBG005332.
InParanoid	P51801.
KO	K05018.
OMA	PRIRSRH.
OrthoDB	EOG4KD6KM.
PhylomeDB	P51801.
Gene expression databases
ArrayExpress	P51801.
Bgee	P51801.
CleanEx	HS_CLCNKB.
Genevestigator	P51801.
GermOnline	ENSG00000184908. Homo sapiens.
Family and domain databases
Gene3D	1.10.3080.10. 2 hits.
InterPro	IPR014743. Cl-channel_core. IPR001807. Cl-channel_volt-gated. IPR002250. Cl_channel-K. IPR000644. Cysta_beta_synth_core. [Graphical view]
Pfam	PF00571. CBS. 2 hits. PF00654. Voltage_CLC. 1 hit. [Graphical view]
PRINTS	PR00762. CLCHANNEL. PR01119. CLCHANNELKDY.
SMART	SM00116. CBS. 2 hits. [Graphical view]
SUPFAM	SSF81340. Cl-channel_core. 1 hit.
PROSITE	PS51371. CBS. 2 hits. [Graphical view]
ProtoNet	Search...
Other
GenomeRNAi	1188.
NextBio	4918.
SOURCE	Search...

Entry information

Entry name

CLCKB_HUMAN

Accession

Primary (citable) accession number: P51801
Secondary accession number(s): B3KUY3, Q5T5Q7, Q5T5Q8

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	February 9, 2010
Last modified:	May 29, 2013
This is version 124 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.