P22748 (CAH4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Carbonic anhydrase 4
EC=4.2.1.1

Alternative name(s):
Carbonate dehydratase IV
Carbonic anhydrase IV
Short name=CA-IV

Gene names

Name:

CA4

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	312 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Reversible hydration of carbon dioxide. May stimulate the sodium/bicarbonate transporter activity of SLC4A4 that acts in pH homeostasis. It is essential for acid overload removal from the retina and retina epithelium, and acid release in the choriocapillaris in the choroid. Ref.17
Catalytic activity	H2CO3 = CO2 + H2O.
Cofactor	Zinc.
Enzyme regulation	Activated by histamine, L-adrenaline, D-phenylalanine, L- and D-histidine. Inhibited by coumarins, saccharin, sulfonamide derivatives such as acetazolamide and Foscarnet (phosphonoformate trisodium salt). Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14
Subunit structure	Interacts with SLC4A4. Ref.17
Subcellular location	Cell membrane; Lipid-anchor › GPI-anchor Ref.6.
Tissue specificity	Expressed in the endothelium of the choriocapillaris in eyes (at protein level). Not expressed in the retinal epithelium at detectable levels. Ref.17
Involvement in disease	Retinitis pigmentosa 17 (RP17) [MIM:600852]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. Note: The disease is caused by mutations affecting the gene represented in this entry. Defective acid overload removal from retina and retinal epithelium, due to mutant CA4, is responsible for photoreceptor degeneration, indicating that impaired pH homeostasis is the most likely cause underlying the RP17 phenotype. Ref.17
Sequence similarities	Belongs to the alpha-carbonic anhydrase family.
Biophysicochemical properties	Kinetic parameters: KM=21.5 mM for CO2 Ref.14

Ontologies

Keywords
Cellular component	Cell membrane Membrane
Coding sequence diversity	Polymorphism
Disease	Disease mutation Retinitis pigmentosa
Domain	Signal
Ligand	Metal-binding Zinc
Molecular function	Lyase
PTM	Disulfide bond GPI-anchor Glycoprotein Lipoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	bicarbonate transport Inferred from mutant phenotype Ref.17. Source: DFLAT one-carbon metabolic process Inferred from electronic annotation. Source: InterPro organ development Inferred from electronic annotation. Source: Compara response to drug Inferred from electronic annotation. Source: Compara response to steroid hormone stimulus Inferred from electronic annotation. Source: Compara small molecule metabolic process Traceable author statement. Source: Reactome
Cellular_component	Golgi apparatus Inferred from direct assay PubMed 17409381. Source: DFLAT anchored to external side of plasma membrane Inferred from direct assay PubMed 17409381. Source: DFLAT apical plasma membrane Inferred from direct assay PubMed 17409381. Source: DFLAT brush border membrane Inferred from direct assay PubMed 17409381. Source: DFLAT endoplasmic reticulum-Golgi intermediate compartment Inferred from direct assay PubMed 17409381. Source: DFLAT perinuclear region of cytoplasm Inferred from direct assay PubMed 17409381. Source: DFLAT rough endoplasmic reticulum Inferred from direct assay PubMed 17409381. Source: DFLAT sarcolemma Inferred from electronic annotation. Source: Compara sarcoplasmic reticulum Inferred from electronic annotation. Source: Compara secretory granule membrane Inferred from direct assay PubMed 17409381. Source: DFLAT trans-Golgi network Inferred from direct assay PubMed 17409381. Source: DFLAT transport vesicle membrane Inferred from direct assay PubMed 17409381. Source: DFLAT
Molecular_function	carbonate dehydratase activity Traceable author statement. Source: Reactome zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 18

18

Ref.4

Chain

19 – 284

266

Carbonic anhydrase 4

PRO_0000004226

Propeptide

285 – 312

28

Removed in mature form

PRO_0000004227

Regions

Region

225 – 226

2

Substrate binding Probable

Sites

Active site

88

1

Proton acceptor By similarity

Metal binding

115

1

Zinc; catalytic

Metal binding

117

1

Zinc; catalytic

Metal binding

140

1

Zinc; catalytic

Amino acid modifications

Lipidation

284

1

GPI-anchor amidated serine Ref.6

Disulfide bond

24 ↔ 36

Ref.5

Disulfide bond

46 ↔ 229

Ref.5

Natural variations

Natural variant

14

1

R → W in RP17; abolishes interaction with SLC4A4. Impaired SLC4A4 cotransporter activity stimulation. Ref.17

VAR_024749

Natural variant

219

1

R → S in RP17; no catalytic activity. Impaired SLC4A4 cotransporter activity stimulation. Ref.17

VAR_024750

Natural variant

237

1

V → L.
Corresponds to variant rs2229178 [ dbSNP | Ensembl ].

VAR_048680

Experimental info

Mutagenesis

284

1

S → F: Loss of C-terminal domain removal and inactivation. Ref.6

Sequence conflict

24

1

C → E AA sequence Ref.4

Secondary structure

1

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312

Helix Strand Turn

Details...

Helix

26 – 29

4

Helix

39 – 41

3

Turn

44 – 47

4

Beta strand

48 – 50

3

Helix

58 – 60

3

Beta strand

61 – 63

3

Beta strand

70 – 77

8

Beta strand

82 – 85

4

Beta strand

87 – 93

7

Beta strand

99 – 102

4

Beta strand

109 – 118

10

Beta strand

127 – 130

4

Beta strand

136 – 145

10

Beta strand

162 – 175

14

Helix

178 – 180

3

Helix

181 – 186

6

Helix

187 – 189

3

Beta strand

196 – 198

3

Helix

205 – 207

3

Helix

211 – 214

4

Beta strand

217 – 222

6

Beta strand

233 – 240

8

Beta strand

242 – 245

4

Helix

246 – 255

10

Beta strand

257 – 259

3

Beta strand

264 – 266

3

Sequences

	Sequence		Length	Mass (Da)
	P22748 [UniParc]. Last modified August 1, 1992. Version 2. Checksum: EF5F182474ABE9B0	FASTA	312	35,032
	10 20 30 40 50 60 MRMLLALLAL SAARPSASAE SHWCYEVQAE SSNYPCLVPV KWGGNCQKDR QSPINIVTTK 70 80 90 100 110 120 AKVDKKLGRF FFSGYDKKQT WTVQNNGHSV MMLLENKASI SGGGLPAPYQ AKQLHLHWSD 130 140 150 160 170 180 LPYKGSEHSL DGEHFAMEMH IVHEKEKGTS RNVKEAQDPE DEIAVLAFLV EAGTQVNEGF 190 200 210 220 230 240 QPLVEALSNI PKPEMSTTMA ESSLLDLLPK EEKLRHYFRY LGSLTTPTCD EKVVWTVFRE 250 260 270 280 290 300 PIQLHREQIL AFSQKLYYDK EQTVSMKDNV RPLQQLGQRT VIKSGAPGRP LPWALPALLG 310 PMLACLLAGF LR

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human carbonic anhydrase IV: cDNA cloning, sequence comparison, and expression in COS cell membranes." Okuyama T., Sato S., Zhu X.L., Waheed A., Sly W.S. Proc. Natl. Acad. Sci. U.S.A. 89:1315-1319(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Genomic organization and localization of gene for human carbonic anhydrase IV to chromosome 17q." Okuyama T., Batanian J.R., Sly W.S. Genomics 16:678-684(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain and Placenta.
[4]	"Carbonic anhydrase IV from human lung. Purification, characterization, and comparison with membrane carbonic anhydrase from human kidney." Zhu X.L., Sly W.S. J. Biol. Chem. 265:8795-8801(1990) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 19-35; 113-123 AND 233-239. Tissue: Lung.
[5]	"Carbonic anhydrase IV: purification of a secretory form of the recombinant human enzyme and identification of the positions and importance of its disulfide bonds." Waheed A., Okuyama T., Heyduk T., Sly W.S. Arch. Biochem. Biophys. 333:432-438(1996) [PubMed] [Europe PMC] [Abstract] Cited for: DISULFIDE BONDS.
[6]	"Carbonic anhydrase IV: role of removal of C-terminal domain in glycosylphosphatidylinositol anchoring and realization of enzyme activity." Okuyama T., Waheed A., Kusumoto W., Zhu X.L., Sly W.S. Arch. Biochem. Biophys. 320:315-322(1995) [PubMed] [Europe PMC] [Abstract] Cited for: GPI-ANCHOR AT SER-284, MUTAGENESIS OF SER-284.
[7]	"Carbonic anhydrase activators. Activation of isozymes I, II, IV, VA, VII, and XIV with l- and d-histidine and crystallographic analysis of their adducts with isoform II: engineering proton-transfer processes within the active site of an enzyme." Temperini C., Scozzafava A., Vullo D., Supuran C.T. Chemistry 12:7057-7066(2006) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION.
[8]	"Carbonic anhydrase activators. Activation of isoforms I, II, IV, VA, VII, and XIV with L- and D-phenylalanine and crystallographic analysis of their adducts with isozyme II: stereospecific recognition within the active site of an enzyme and its consequences for the drug design." Temperini C., Scozzafava A., Vullo D., Supuran C.T. J. Med. Chem. 49:3019-3027(2006) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION.
[9]	"Saccharin inhibits carbonic anhydrases: possible explanation for its unpleasant metallic aftertaste." Koehler K., Hillebrecht A., Schulze Wischeler J., Innocenti A., Heine A., Supuran C.T., Klebe G. Angew. Chem. Int. Ed. Engl. 46:7697-7699(2007) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION.
[10]	"Carbonic anhydrase activators: L-Adrenaline plugs the active site entrance of isozyme II, activating better isoforms I, IV, VA, VII, and XIV." Temperini C., Innocenti A., Scozzafava A., Mastrolorenzo A., Supuran C.T. Bioorg. Med. Chem. Lett. 17:628-635(2007) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION.
[11]	"Phosph(on)ate as a zinc-binding group in metalloenzyme inhibitors: X-ray crystal structure of the antiviral drug foscarnet complexed to human carbonic anhydrase I." Temperini C., Innocenti A., Guerri A., Scozzafava A., Rusconi S., Supuran C.T. Bioorg. Med. Chem. Lett. 17:2210-2215(2007) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION.
[12]	"A thiabendazole sulfonamide shows potent inhibitory activity against mammalian and nematode alpha-carbonic anhydrases." Crocetti L., Maresca A., Temperini C., Hall R.A., Scozzafava A., Muehlschlegel F.A., Supuran C.T. Bioorg. Med. Chem. Lett. 19:1371-1375(2009) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION.
[13]	"Non-zinc mediated inhibition of carbonic anhydrases: coumarins are a new class of suicide inhibitors." Maresca A., Temperini C., Vu H., Pham N.B., Poulsen S.-A., Scozzafava A., Quinn R.J., Supuran C.T. J. Am. Chem. Soc. 131:3057-3062(2009) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION.
[14]	"Crystal structure of human carbonic anhydrase XIII and its complex with the inhibitor acetazolamide." Di Fiore A., Monti S.M., Hilvo M., Parkkila S., Romano V., Scaloni A., Pedone C., Scozzafava A., Supuran C.T., De Simone G. Proteins 74:164-175(2009) [PubMed] [Europe PMC] [Abstract] Cited for: BIOPHYSICOCHEMICAL PROPERTIES, ENZYME REGULATION.
[15]	"Crystal structure of the secretory form of membrane-associated human carbonic anhydrase IV at 2.8-A resolution." Stams T., Nair S.K., Okuyama T., Waheed A., Sly W.S., Christianson D.W. Proc. Natl. Acad. Sci. U.S.A. 93:13589-13594(1996) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 19-284 IN COMPLEX WITH ZINC ION.
[16]	"Thioether benzenesulfonamide inhibitors of carbonic anhydrases II and IV: structure-based drug design, synthesis, and biological evaluation." Vernier W.F., Chong W., Rewolinski D., Greasley S., Pauly T.A., Shaw M., Dinh D.M., Ferre R.A.A., Meador J.W. III, Nukui S., Ornelas M., Paz R.L., Reyner E. Bioorg. Med. Chem. 18:3307-3319(2010) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 19-284 IN COMPLEX WITH INHIBITORS.
[17]	"Mutant carbonic anhydrase 4 impairs pH regulation and causes retinal photoreceptor degeneration." Yang Z., Alvarez B.V., Chakarova C., Jiang L., Karan G., Frederick J.M., Zhao Y., Sauve Y., Li X., Zrenner E., Wissinger B., Den Hollander A.I., Katz B., Baehr W., Cremers F.P., Casey J.R., Bhattacharya S.S., Zhang K. Hum. Mol. Genet. 14:255-265(2005) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS RP17 TRP-14 AND SER-219, FUNCTION, TISSUE SPECIFICITY, INTERACTION WITH SLC4A4.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M83670 mRNA. Translation: AAA35630.1.
L10955 , L10951, L10953, L10954 Genomic DNA. Translation: AAA35625.1. Sequence problems.
L10955, L10954 Genomic DNA. Translation: AAA35626.1. Sequence problems.
BC057792 mRNA. Translation: AAH57792.1.
BC069649 mRNA. Translation: AAH69649.1.
BC074768 mRNA. Translation: AAH74768.1.

IPI

IPI00027466.

PIR

CRHU4. A45745.

RefSeq

NP_000708.1. NM_000717.3.

UniGene

Hs.89485.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1ZNC	X-ray	2.80	A/B	19-284	[»]
3F7B	X-ray	2.05	A/B	19-284	[»]
3F7U	X-ray	2.00	A/B/C/D	19-284	[»]
3FW3	X-ray	1.72	A/B	19-284	[»]

ProteinModelPortal

P22748.

ModBase

Search...

Protein-protein interaction databases

IntAct

P22748. 2 interactions.

STRING

9606.ENSP00000300900.

PTM databases

PhosphoSite

P22748.

Polymorphism databases

DMDM

115465.

Proteomic databases

PaxDb

P22748.

PRIDE

P22748.

Protocols and materials databases

DNASU

762.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000300900; ENSP00000300900; ENSG00000167434.

GeneID

762.

KEGG

hsa:762.

UCSC

uc002iym.4. human.

Organism-specific databases

CTD

762.

GeneCards

GC17P058227.

HGNC

HGNC:1375. CA4.

HPA

HPA011089.
HPA017258.

MIM

114760. gene.
600852. phenotype.

neXtProt

NX_P22748.

Orphanet

791. Retinitis pigmentosa.

PharmGKB

PA25991.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG3338.

HOGENOM

HOG000112637.

HOVERGEN

HBG002837.

InParanoid

P22748.

KO

K01672.

OMA

SMKDNVR.

OrthoDB

EOG4FXR84.

PhylomeDB

P22748.

Enzyme and pathway databases

BRENDA

4.2.1.1. 2681.

Reactome

REACT_111217. Metabolism.

SABIO-RK

P22748.

Gene expression databases

ArrayExpress

P22748.

Bgee

P22748.

CleanEx

HS_CA4.

Genevestigator

P22748.

GermOnline

ENSG00000167434. Homo sapiens.

Family and domain databases

Gene3D

3.10.200.10. 1 hit.

InterPro

IPR001148. Carbonic_anhydrase_a.
IPR023561. Carbonic_anhydrase_a-class.
IPR018338. Carbonic_anhydrase_a-class_CS.
IPR018343. Carbonic_anhydrase_CA4.
[Graphical view]

PANTHER

PTHR18952. PTHR18952. 1 hit.
PTHR18952:SF5. PTHR18952:SF5. 1 hit.

Pfam

PF00194. Carb_anhydrase. 1 hit.
[Graphical view]

SMART

SM01057. Carb_anhydrase. 1 hit.
[Graphical view]

SUPFAM

SSF51069. Euk_COanhd. 1 hit.

PROSITE

PS00162. ALPHA_CA_1. 1 hit.
PS51144. ALPHA_CA_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P22748.

ChEMBL

CHEMBL3729.

DrugBank

DB00436. Bendroflumethiazide.
DB00562. Benzthiazide.
DB00880. Chlorothiazide.
DB00606. Cyclothiazide.
DB01119. Diazoxide.
DB00999. Hydrochlorothiazide.
DB00774. Hydroflumethiazide.
DB00232. Methyclothiazide.
DB01325. Quinethazone.
DB00273. Topiramate.
DB01021. Trichlormethiazide.

EvolutionaryTrace

P22748.

GenomeRNAi

762.

NextBio

3082.

SOURCE

Search...

Entry information

Entry name

CAH4_HUMAN

Accession

Primary (citable) accession number: P22748

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1991
Last sequence update:	August 1, 1992
Last modified:	May 1, 2013
This is version 145 of the entry and version 2 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.