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Database: UniProt
Entry: CARP4_CANAL
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Original site: CARP4_CANAL 
ID   CARP4_CANAL             Reviewed;         417 AA.
AC   Q5A8N2; A0A1D8PQ73;
DT   13-NOV-2013, integrated into UniProtKB/Swiss-Prot.
DT   26-APR-2005, sequence version 1.
DT   24-JAN-2024, entry version 121.
DE   RecName: Full=Secreted aspartic protease 4 {ECO:0000303|PubMed:7907585};
DE            Short=ACP 4 {ECO:0000305};
DE            Short=Aspartate protease 4 {ECO:0000305};
DE            EC=3.4.23.24 {ECO:0000269|PubMed:21646240, ECO:0000269|PubMed:27390786};
DE   AltName: Full=Candidapepsin-4 {ECO:0000305};
DE   Flags: Precursor;
GN   Name=SAP4 {ECO:0000303|PubMed:7907585}; OrderedLocusNames=CAALFM_C603500CA;
GN   ORFNames=CaO19.13139, CaO19.5716;
OS   Candida albicans (strain SC5314 / ATCC MYA-2876) (Yeast).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Saccharomycotina; Saccharomycetes;
OC   Saccharomycetales; Debaryomycetaceae; Candida/Lodderomyces clade; Candida.
OX   NCBI_TaxID=237561;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=SC5314 / ATCC MYA-2876;
RX   PubMed=15123810; DOI=10.1073/pnas.0401648101;
RA   Jones T., Federspiel N.A., Chibana H., Dungan J., Kalman S., Magee B.B.,
RA   Newport G., Thorstenson Y.R., Agabian N., Magee P.T., Davis R.W.,
RA   Scherer S.;
RT   "The diploid genome sequence of Candida albicans.";
RL   Proc. Natl. Acad. Sci. U.S.A. 101:7329-7334(2004).
RN   [2]
RP   GENOME REANNOTATION.
RC   STRAIN=SC5314 / ATCC MYA-2876;
RX   PubMed=17419877; DOI=10.1186/gb-2007-8-4-r52;
RA   van het Hoog M., Rast T.J., Martchenko M., Grindle S., Dignard D.,
RA   Hogues H., Cuomo C., Berriman M., Scherer S., Magee B.B., Whiteway M.,
RA   Chibana H., Nantel A., Magee P.T.;
RT   "Assembly of the Candida albicans genome into sixteen supercontigs aligned
RT   on the eight chromosomes.";
RL   Genome Biol. 8:RESEARCH52.1-RESEARCH52.12(2007).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND GENOME REANNOTATION.
RC   STRAIN=SC5314 / ATCC MYA-2876;
RX   PubMed=24025428; DOI=10.1186/gb-2013-14-9-r97;
RA   Muzzey D., Schwartz K., Weissman J.S., Sherlock G.;
RT   "Assembly of a phased diploid Candida albicans genome facilitates allele-
RT   specific measurements and provides a simple model for repeat and indel
RT   structure.";
RL   Genome Biol. 14:RESEARCH97.1-RESEARCH97.14(2013).
RN   [4]
RP   IDENTIFICATION.
RX   PubMed=7907585; DOI=10.1128/jb.176.6.1702-1710.1994;
RA   Miyasaki S.H., White T.C., Agabian N.;
RT   "A fourth secreted aspartyl proteinase gene (SAP4) and a CARE2 repetitive
RT   element are located upstream of the SAP1 gene in Candida albicans.";
RL   J. Bacteriol. 176:1702-1710(1994).
RN   [5]
RP   FUNCTION.
RX   PubMed=11478679; DOI=10.1099/0022-1317-50-8-743;
RA   Schaller M., Januschke E., Schackert C., Woerle B., Korting H.C.;
RT   "Different isoforms of secreted aspartyl proteinases (Sap) are expressed by
RT   Candida albicans during oral and cutaneous candidosis in vivo.";
RL   J. Med. Microbiol. 50:743-747(2001).
RN   [6]
RP   FUNCTION.
RX   PubMed=12065511; DOI=10.1128/iai.70.7.3689-3700.2002;
RA   Felk A., Kretschmar M., Albrecht A., Schaller M., Beinhauer S.,
RA   Nichterlein T., Sanglard D., Korting H.C., Schafer W., Hube B.;
RT   "Candida albicans hyphal formation and the expression of the Efg1-regulated
RT   proteinases Sap4 to Sap6 are required for the invasion of parenchymal
RT   organs.";
RL   Infect. Immun. 70:3689-3700(2002).
RN   [7]
RP   ACTIVITY REGULATION.
RX   PubMed=12203839; DOI=10.1002/jmr.568;
RA   Farley P.C., Christeller J.T., Sullivan M.E., Sullivan P.A., Laing W.A.;
RT   "Analysis of the interaction between the aspartic peptidase inhibitor SQAPI
RT   and aspartic peptidases using surface plasmon resonance.";
RL   J. Mol. Recognit. 15:135-144(2002).
RN   [8]
RP   INDUCTION.
RX   PubMed=15731084; DOI=10.1128/iai.73.3.1828-1835.2005;
RA   Taylor B.N., Staib P., Binder A., Biesemeier A., Sehnal M., Rollinghoff M.,
RA   Morschhauser J., Schroppel K.;
RT   "Profile of Candida albicans-secreted aspartic proteinase elicited during
RT   vaginal infection.";
RL   Infect. Immun. 73:1828-1835(2005).
RN   [9]
RP   FUNCTION.
RX   PubMed=21540243; DOI=10.1242/dmm.006627;
RA   Glittenberg M.T., Kounatidis I., Christensen D., Kostov M., Kimber S.,
RA   Roberts I., Ligoxygakis P.;
RT   "Pathogen and host factors are needed to provoke a systemic host response
RT   to gastrointestinal infection of Drosophila larvae by Candida albicans.";
RL   Dis. Model. Mech. 4:515-525(2011).
RN   [10]
RP   CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX   PubMed=21646240; DOI=10.1093/jb/mvr073;
RA   Aoki W., Kitahara N., Miura N., Morisaka H., Yamamoto Y., Kuroda K.,
RA   Ueda M.;
RT   "Comprehensive characterization of secreted aspartic proteases encoded by a
RT   virulence gene family in Candida albicans.";
RL   J. Biochem. 150:431-438(2011).
RN   [11]
RP   INDUCTION.
RX   PubMed=22433888;
RA   Khodavandi A., Alizadeh F., Harmal N.S., Sidik S.M., Othman F., Sekawi Z.,
RA   Chong P.P.;
RT   "Expression analysis of SIR2 and SAPs1-4 gene expression in Candida
RT   albicans treated with allicin compared to fluconazole.";
RL   Trop. Biomed. 28:589-598(2011).
RN   [12]
RP   INDUCTION.
RX   PubMed=23484407;
RA   Staniszewska M., Bondaryk M., Siennicka K., Kurek A., Orlowski J.,
RA   Schaller M., Kurzatkowski W.;
RT   "In vitro study of secreted aspartyl proteinases Sap1 to Sap3 and Sap4 to
RT   Sap6 expression in Candida albicans pleomorphic forms.";
RL   Pol. J. Microbiol. 61:247-256(2012).
RN   [13]
RP   FUNCTION.
RX   PubMed=23927842; DOI=10.1016/j.peptides.2013.07.023;
RA   Bochenska O., Rapala-Kozik M., Wolak N., Bras G., Kozik A., Dubin A.,
RA   Aoki W., Ueda M., Mak P.;
RT   "Secreted aspartic peptidases of Candida albicans liberate bactericidal
RT   hemocidins from human hemoglobin.";
RL   Peptides 48:49-58(2013).
RN   [14]
RP   FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX   PubMed=27390786; DOI=10.18388/abp.2016_1318;
RA   Bochenska O., Rapala-Kozik M., Wolak N., Aoki W., Ueda M., Kozik A.;
RT   "The action of ten secreted aspartic proteases of pathogenic yeast Candida
RT   albicans on major human salivary antimicrobial peptide, histatin 5.";
RL   Acta Biochim. Pol. 63:403-410(2016).
CC   -!- FUNCTION: Secreted aspartic peptidases (SAPs) are a group of ten acidic
CC       hydrolases considered as key virulence factors (PubMed:11478679,
CC       PubMed:12065511, PubMed:21540243). These enzymes supply the fungus with
CC       nutrient amino acids as well as are able to degrade the selected host's
CC       proteins involved in the immune defense (PubMed:11478679,
CC       PubMed:12065511, PubMed:21540243). Moreover, acts toward human
CC       hemoglobin though limited proteolysis to generate a variety of
CC       antimicrobial hemocidins, enabling to compete with the other
CC       microorganisms of the same physiological niche using the microbicidal
CC       peptides generated from the host protein (PubMed:23927842).
CC       {ECO:0000269|PubMed:11478679, ECO:0000269|PubMed:12065511,
CC       ECO:0000269|PubMed:21540243, ECO:0000269|PubMed:23927842}.
CC   -!- FUNCTION: Plays a key role in defense against host by cleaving
CC       histatin-5 (Hst 5), a peptide from human saliva that carries out
CC       fungicidal activity (PubMed:27390786). The cleavage rate decreases in
CC       an order of SAP2 > SAP9 > SAP3 > SAP7 > SAP4 > SAP1 > SAP8
CC       (PubMed:27390786). The first cleavage occurs between residues 'Lys-17'
CC       and 'His-18' of Hst 5, giving DSHAKRHHGYKRKFHEK and HHSHRGY peptides
CC       (PubMed:27390786). Simultaneously, the DSHAKRHHGY and KRKFHEKHHSHRGY
CC       peptides are also formed (PubMed:27390786).
CC       {ECO:0000269|PubMed:27390786}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Preferential cleavage at the carboxyl of hydrophobic amino
CC         acids, but fails to cleave 15-Leu-|-Tyr-16, 16-Tyr-|-Leu-17 and 24-
CC         Phe-|-Phe-25 of insulin B chain. Activates trypsinogen, and degrades
CC         keratin.; EC=3.4.23.24; Evidence={ECO:0000269|PubMed:21646240,
CC         ECO:0000269|PubMed:27390786};
CC   -!- ACTIVITY REGULATION: Activity is inhibited by squash aspartic peptidase
CC       inhibitor (SQAPI). {ECO:0000269|PubMed:12203839}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       pH dependence:
CC         Optimum pH is 5.0 using casein-resorufin as substrate, and 6.0-7.0,
CC         the pH of the saliva, for cleavage of Hst 5.
CC         {ECO:0000269|PubMed:21646240, ECO:0000269|PubMed:27390786};
CC   -!- SUBUNIT: Monomer. {ECO:0000250|UniProtKB:P0CS83}.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:P0CY27}.
CC   -!- INDUCTION: Expressed during development of germ tubes, pseudohyphae and
CC       true hyphae (PubMed:23484407). Induced during host infection
CC       (PubMed:15731084). Expression is suppressed by fluconazole
CC       (PubMed:22433888). {ECO:0000269|PubMed:15731084,
CC       ECO:0000269|PubMed:22433888, ECO:0000269|PubMed:23484407}.
CC   -!- SIMILARITY: Belongs to the peptidase A1 family. {ECO:0000305}.
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DR   EMBL; CP017628; AOW30280.1; -; Genomic_DNA.
DR   RefSeq; XP_718054.1; XM_712961.1.
DR   AlphaFoldDB; Q5A8N2; -.
DR   SMR; Q5A8N2; -.
DR   STRING; 237561.Q5A8N2; -.
DR   MEROPS; A01.062; -.
DR   GlyCosmos; Q5A8N2; 1 site, No reported glycans.
DR   EnsemblFungi; C6_03500C_A-T; C6_03500C_A-T-p1; C6_03500C_A.
DR   GeneID; 3640257; -.
DR   KEGG; cal:CAALFM_C603500CA; -.
DR   CGD; CAL0000194858; SAP4.
DR   VEuPathDB; FungiDB:C6_03500C_A; -.
DR   eggNOG; KOG1339; Eukaryota.
DR   HOGENOM; CLU_013253_9_1_1; -.
DR   InParanoid; Q5A8N2; -.
DR   OMA; NEAYVAD; -.
DR   OrthoDB; 615305at2759; -.
DR   BRENDA; 3.4.23.24; 1096.
DR   PHI-base; PHI:6786; -.
DR   PHI-base; PHI:6792; -.
DR   PHI-base; PHI:6807; -.
DR   PHI-base; PHI:6814; -.
DR   PRO; PR:Q5A8N2; -.
DR   Proteomes; UP000000559; Chromosome 6.
DR   GO; GO:0005576; C:extracellular region; IDA:CGD.
DR   GO; GO:0009277; C:fungal-type cell wall; IBA:GO_Central.
DR   GO; GO:0004190; F:aspartic-type endopeptidase activity; IDA:CGD.
DR   GO; GO:0042783; P:evasion of host immune response; IEP:CGD.
DR   GO; GO:0031505; P:fungal-type cell wall organization; IBA:GO_Central.
DR   GO; GO:0044416; P:induction by symbiont of host defense response; IMP:CGD.
DR   GO; GO:0006508; P:proteolysis; IDA:CGD.
DR   CDD; cd05474; SAP_like; 1.
DR   Gene3D; 2.40.70.10; Acid Proteases; 2.
DR   InterPro; IPR001461; Aspartic_peptidase_A1.
DR   InterPro; IPR001969; Aspartic_peptidase_AS.
DR   InterPro; IPR033121; PEPTIDASE_A1.
DR   InterPro; IPR021109; Peptidase_aspartic_dom_sf.
DR   InterPro; IPR033876; SAP-like.
DR   PANTHER; PTHR47966:SF65; ASPARTIC-TYPE ENDOPEPTIDASE; 1.
DR   PANTHER; PTHR47966; BETA-SITE APP-CLEAVING ENZYME, ISOFORM A-RELATED; 1.
DR   Pfam; PF00026; Asp; 1.
DR   PRINTS; PR00792; PEPSIN.
DR   SUPFAM; SSF50630; Acid proteases; 1.
DR   PROSITE; PS00141; ASP_PROTEASE; 2.
DR   PROSITE; PS51767; PEPTIDASE_A1; 1.
PE   1: Evidence at protein level;
KW   Aspartyl protease; Cleavage on pair of basic residues; Disulfide bond;
KW   Glycoprotein; Hydrolase; Metal-binding; Protease; Reference proteome;
KW   Repeat; Secreted; Signal; Virulence; Zinc; Zymogen.
FT   SIGNAL          1..18
FT                   /evidence="ECO:0000255"
FT   PROPEP          19..75
FT                   /note="Activation peptide"
FT                   /evidence="ECO:0000305"
FT                   /id="PRO_0000424296"
FT   CHAIN           76..417
FT                   /note="Secreted aspartic protease 4"
FT                   /id="PRO_0000424297"
FT   DOMAIN          89..403
FT                   /note="Peptidase A1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01103"
FT   ACT_SITE        107
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10094"
FT   ACT_SITE        293
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10094"
FT   BINDING         107..109
FT                   /ligand="pepstatin A"
FT                   /ligand_id="ChEBI:CHEBI:190525"
FT                   /ligand_note="inhibitor"
FT                   /evidence="ECO:0000250|UniProtKB:P0CY29"
FT   BINDING         160..161
FT                   /ligand="pepstatin A"
FT                   /ligand_id="ChEBI:CHEBI:190525"
FT                   /ligand_note="inhibitor"
FT                   /evidence="ECO:0000250|UniProtKB:P0CY29"
FT   BINDING         267
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:P0CY29"
FT   BINDING         293..297
FT                   /ligand="pepstatin A"
FT                   /ligand_id="ChEBI:CHEBI:190525"
FT                   /ligand_note="inhibitor"
FT                   /evidence="ECO:0000250|UniProtKB:P0CY29"
FT   CARBOHYD        137
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        122..134
FT                   /evidence="ECO:0000250|UniProtKB:P0CY27"
FT   DISULFID        331..369
FT                   /evidence="ECO:0000250|UniProtKB:P0CY27"
SQ   SEQUENCE   417 AA;  45332 MW;  796346A4469FB60A CRC64;
     MFLQNILSVL AFALLIDAAP VKRSTGFVTL DFNVKRSLVD PKDPTVEVKR SPLFLDIEPT
     EIPVDDTGRN DVGKRGPVAV KLDNEIITYS ADITIGSNNQ KLSVIVDTGS SDLWVPDSNA
     VCIPKWPGDR GDFCKNNGSY SPAASSTSKN LNTPFEIKYA DGSVAQGNLY QDTVGIGGVS
     VRDQLFANVR STSAHKGILG IGFQSNEATR TPYDNLPITL KKQGIISKNA YSLFLNSPEA
     SSGQIIFGGI DKAKYSGSLV DLPITSDRTL SVGLRSVNVM GQNVNVNAGV LLDSGTTISY
     FTPNIARSII YALGGQVHYD SSGNEAYVAD CKTSGTVDFQ FDRNLKISVP ASEFLYQLYY
     TNGEPYPKCE IRVRESEDNI LGDNFMRSAY IVYDLDDRKI SMAQVKYTSQ SNIVAIN
//
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