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Protein

Carbonic anhydrase 4

Gene

CA4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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.1 Publication

Catalytic activityi

H2CO3 = CO2 + H2O.

Cofactori

Zn2+1 Publication

Enzyme regulationi

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).8 Publications

Kineticsi

  1. KM=21.5 mM for CO21 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Active sitei88Proton acceptorBy similarity1
    Metal bindingi115Zinc; catalytic1 Publication1
    Metal bindingi117Zinc; catalytic1 Publication1
    Metal bindingi140Zinc; catalytic1 Publication1

    GO - Molecular functioni

    GO - Biological processi

    • bicarbonate transport Source: DFLAT
    • one-carbon metabolic process Source: InterPro

    Keywordsi

    Molecular functionLyase
    LigandMetal-binding, Zinc

    Enzyme and pathway databases

    BRENDAi4.2.1.1 2681
    ReactomeiR-HSA-1237044 Erythrocytes take up carbon dioxide and release oxygen
    R-HSA-1247673 Erythrocytes take up oxygen and release carbon dioxide
    R-HSA-1475029 Reversible hydration of carbon dioxide
    SABIO-RKiP22748

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Carbonic anhydrase 4 (EC:4.2.1.1)
    Alternative name(s):
    Carbonate dehydratase IV
    Carbonic anhydrase IV
    Short name:
    CA-IV
    Gene namesi
    Name:CA4
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 17

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000167434.9
    HGNCiHGNC:1375 CA4
    MIMi114760 gene
    neXtProtiNX_P22748

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Keywords - Cellular componenti

    Cell membrane, Membrane

    Pathology & Biotechi

    Involvement in diseasei

    Retinitis pigmentosa 17 (RP17)3 Publications
    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.
    Disease descriptionA 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.
    See also OMIM:600852
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_07143012A → T in RP17. 1 Publication1
    Natural variantiVAR_02474914R → W in RP17; abolishes interaction with SLC4A4; impaired SLC4A4 cotransporter activity stimulation. 1 PublicationCorresponds to variant dbSNP:rs104894559Ensembl.1
    Natural variantiVAR_07143169R → H in RP17; has no effect on catalytic activity; loss of interaction with SLC4A4. 1 PublicationCorresponds to variant dbSNP:rs121434552Ensembl.1
    Natural variantiVAR_024750219R → S in RP17; no catalytic activity; impaired SLC4A4 cotransporter activity stimulation. 1 PublicationCorresponds to variant dbSNP:rs121434551Ensembl.1

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi284S → F: Loss of C-terminal domain removal and inactivation. 1 Publication1

    Keywords - Diseasei

    Disease mutation, Retinitis pigmentosa

    Organism-specific databases

    DisGeNETi762
    GeneReviewsiCA4
    MalaCardsiCA4
    MIMi600852 phenotype
    OpenTargetsiENSG00000167434
    Orphaneti791 Retinitis pigmentosa
    PharmGKBiPA25991

    Chemistry databases

    ChEMBLiCHEMBL3729
    DrugBankiDB00819 Acetazolamide
    DB00436 Bendroflumethiazide
    DB00562 Benzthiazide
    DB01194 Brinzolamide
    DB00880 Chlorothiazide
    DB00606 Cyclothiazide
    DB01144 Diclofenamide
    DB00869 Dorzolamide
    DB08846 Ellagic Acid
    DB00311 Ethoxzolamide
    DB00999 Hydrochlorothiazide
    DB00774 Hydroflumethiazide
    DB00703 Methazolamide
    DB00232 Methyclothiazide
    DB09460 Sodium carbonate
    DB00273 Topiramate
    DB01021 Trichlormethiazide
    DB00909 Zonisamide
    GuidetoPHARMACOLOGYi2599

    Polymorphism and mutation databases

    BioMutaiCA4
    DMDMi115465

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Signal peptidei1 – 181 PublicationAdd BLAST18
    ChainiPRO_000000422619 – 284Carbonic anhydrase 4Add BLAST266
    PropeptideiPRO_0000004227285 – 312Removed in mature formAdd BLAST28

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Disulfide bondi24 ↔ 361 Publication
    Disulfide bondi46 ↔ 2291 Publication
    Lipidationi284GPI-anchor amidated serine1 Publication1

    Keywords - PTMi

    Disulfide bond, Glycoprotein, GPI-anchor, Lipoprotein

    Proteomic databases

    EPDiP22748
    PaxDbiP22748
    PeptideAtlasiP22748
    PRIDEiP22748

    PTM databases

    iPTMnetiP22748
    PhosphoSitePlusiP22748

    Expressioni

    Tissue specificityi

    Expressed in the endothelium of the choriocapillaris in eyes (at protein level). Not expressed in the retinal epithelium at detectable levels.1 Publication

    Gene expression databases

    BgeeiENSG00000167434
    CleanExiHS_CA4
    ExpressionAtlasiP22748 baseline and differential
    GenevisibleiP22748 HS

    Organism-specific databases

    HPAiHPA011089
    HPA017258

    Interactioni

    Subunit structurei

    Interacts with SLC4A4.4 Publications

    Protein-protein interaction databases

    BioGridi107217, 7 interactors
    IntActiP22748, 4 interactors
    STRINGi9606.ENSP00000300900

    Chemistry databases

    BindingDBiP22748

    Structurei

    Secondary structure

    1312
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Helixi26 – 29Combined sources4
    Helixi39 – 41Combined sources3
    Turni44 – 47Combined sources4
    Beta strandi48 – 50Combined sources3
    Helixi58 – 60Combined sources3
    Beta strandi61 – 63Combined sources3
    Beta strandi70 – 77Combined sources8
    Beta strandi82 – 85Combined sources4
    Beta strandi87 – 93Combined sources7
    Beta strandi99 – 102Combined sources4
    Beta strandi109 – 118Combined sources10
    Turni122 – 124Combined sources3
    Beta strandi127 – 130Combined sources4
    Beta strandi136 – 145Combined sources10
    Helixi153 – 157Combined sources5
    Beta strandi162 – 175Combined sources14
    Helixi178 – 180Combined sources3
    Helixi181 – 186Combined sources6
    Helixi187 – 189Combined sources3
    Beta strandi196 – 198Combined sources3
    Helixi205 – 207Combined sources3
    Helixi211 – 214Combined sources4
    Beta strandi217 – 222Combined sources6
    Beta strandi233 – 240Combined sources8
    Beta strandi242 – 245Combined sources4
    Helixi246 – 255Combined sources10
    Beta strandi257 – 259Combined sources3
    Beta strandi264 – 266Combined sources3

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    1ZNCX-ray2.80A/B19-284[»]
    3F7BX-ray2.05A/B19-284[»]
    3F7UX-ray2.00A/B/C/D19-284[»]
    3FW3X-ray1.72A/B19-284[»]
    5IPZX-ray2.10A/B/C/D19-284[»]
    5JN8X-ray1.85A/B/C/D19-284[»]
    5JN9X-ray2.10A/B/C/D19-284[»]
    5JNAX-ray2.00A/B/C/D19-284[»]
    5JNCX-ray2.00A/B/C/D19-284[»]
    5KU6X-ray1.80A/B/C/D19-284[»]
    ProteinModelPortaliP22748
    SMRiP22748
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP22748

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini21 – 285Alpha-carbonic anhydrasePROSITE-ProRule annotationAdd BLAST265

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni225 – 226Substrate bindingBy similarity2

    Sequence similaritiesi

    Belongs to the alpha-carbonic anhydrase family.Curated

    Keywords - Domaini

    Signal

    Phylogenomic databases

    eggNOGiKOG0382 Eukaryota
    COG3338 LUCA
    GeneTreeiENSGT00910000144074
    HOGENOMiHOG000112637
    HOVERGENiHBG002837
    InParanoidiP22748
    KOiK18246
    OMAiAESHWCY
    OrthoDBiEOG091G0XFM
    PhylomeDBiP22748
    TreeFamiTF316425

    Family and domain databases

    Gene3Di3.10.200.10, 1 hit
    InterProiView protein in InterPro
    IPR001148 Carbonic_anhydrase_a
    IPR023561 Carbonic_anhydrase_a-class
    IPR018338 Carbonic_anhydrase_a-class_CS
    IPR036398 Carbonic_anhydrase_a_sf
    IPR018343 Carbonic_anhydrase_CA4
    PANTHERiPTHR18952 PTHR18952, 1 hit
    PTHR18952:SF95 PTHR18952:SF95, 1 hit
    PfamiView protein in Pfam
    PF00194 Carb_anhydrase, 1 hit
    SMARTiView protein in SMART
    SM01057 Carb_anhydrase, 1 hit
    SUPFAMiSSF51069 SSF51069, 1 hit
    PROSITEiView protein in PROSITE
    PS00162 ALPHA_CA_1, 1 hit
    PS51144 ALPHA_CA_2, 1 hit

    Sequences (2)i

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

    Isoform 1 (identifier: P22748-1) [UniParc]FASTAAdd to basket

    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.

    « Hide

            10         20         30         40         50
    MRMLLALLAL SAARPSASAE SHWCYEVQAE SSNYPCLVPV KWGGNCQKDR
    60 70 80 90 100
    QSPINIVTTK AKVDKKLGRF FFSGYDKKQT WTVQNNGHSV MMLLENKASI
    110 120 130 140 150
    SGGGLPAPYQ AKQLHLHWSD LPYKGSEHSL DGEHFAMEMH IVHEKEKGTS
    160 170 180 190 200
    RNVKEAQDPE DEIAVLAFLV EAGTQVNEGF QPLVEALSNI PKPEMSTTMA
    210 220 230 240 250
    ESSLLDLLPK EEKLRHYFRY LGSLTTPTCD EKVVWTVFRE PIQLHREQIL
    260 270 280 290 300
    AFSQKLYYDK EQTVSMKDNV RPLQQLGQRT VIKSGAPGRP LPWALPALLG
    310
    PMLACLLAGF LR
    Length:312
    Mass (Da):35,032
    Last modified:August 1, 1992 - v2
    Checksum:iEF5F182474ABE9B0
    GO
    Isoform 2 (identifier: P22748-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         90-106: VMMLLENKASISGGGLP → GWNPGERGLPATGGGTV
         107-312: Missing.

    Note: No experimental confirmation available.
    Show »
    Length:106
    Mass (Da):11,599
    Checksum:i0149FBF9A98FFF2B
    GO

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti24C → E AA sequence (PubMed:2111324).Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_07143012A → T in RP17. 1 Publication1
    Natural variantiVAR_02474914R → W in RP17; abolishes interaction with SLC4A4; impaired SLC4A4 cotransporter activity stimulation. 1 PublicationCorresponds to variant dbSNP:rs104894559Ensembl.1
    Natural variantiVAR_07143169R → H in RP17; has no effect on catalytic activity; loss of interaction with SLC4A4. 1 PublicationCorresponds to variant dbSNP:rs121434552Ensembl.1
    Natural variantiVAR_071432177N → K1 PublicationCorresponds to variant dbSNP:rs185942554Ensembl.1
    Natural variantiVAR_024750219R → S in RP17; no catalytic activity; impaired SLC4A4 cotransporter activity stimulation. 1 PublicationCorresponds to variant dbSNP:rs121434551Ensembl.1
    Natural variantiVAR_048680237V → L. Corresponds to variant dbSNP:rs2229178Ensembl.1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_05597390 – 106VMMLL…GGGLP → GWNPGERGLPATGGGTV in isoform 2. 1 PublicationAdd BLAST17
    Alternative sequenceiVSP_055974107 – 312Missing in isoform 2. 1 PublicationAdd BLAST206

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    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.
    AK289715 mRNA Translation: BAF82404.1
    AK298710 mRNA Translation: BAG60866.1
    CR541766 mRNA Translation: CAG46565.1
    AC025048 Genomic DNA No translation available.
    CH471109 Genomic DNA Translation: EAW94362.1
    BC057792 mRNA Translation: AAH57792.1
    BC069649 mRNA Translation: AAH69649.1
    BC074768 mRNA Translation: AAH74768.1
    CCDSiCCDS11624.1 [P22748-1]
    PIRiA45745 CRHU4
    RefSeqiNP_000708.1, NM_000717.4 [P22748-1]
    XP_016880501.1, XM_017025012.1
    UniGeneiHs.89485

    Genome annotation databases

    EnsembliENST00000300900; ENSP00000300900; ENSG00000167434 [P22748-1]
    ENST00000586876; ENSP00000467465; ENSG00000167434 [P22748-2]
    GeneIDi762
    KEGGihsa:762
    UCSCiuc002iym.5 human [P22748-1]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Similar proteinsi

    Entry informationi

    Entry nameiCAH4_HUMAN
    AccessioniPrimary (citable) accession number: P22748
    Secondary accession number(s): B4DQA4, Q6FHI7
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 1, 1991
    Last sequence update: August 1, 1992
    Last modified: February 28, 2018
    This is version 190 of the entry and version 2 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny 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.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Direct protein sequencing, Reference proteome
    UniProt is an ELIXIR core data resource
    Main funding by: National Institutes of Health