GDPP_BACSU
ID GDPP_BACSU Reviewed; 659 AA.
AC P37484;
DT 01-OCT-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1994, sequence version 1.
DT 03-AUG-2022, entry version 118.
DE RecName: Full=Cyclic-di-AMP phosphodiesterase GdpP {ECO:0000303|PubMed:22211522};
DE Short=c-di-AMP phosphodiesterase YybT {ECO:0000303|PubMed:19901023};
DE EC=3.1.4.59 {ECO:0000269|PubMed:19901023};
DE AltName: Full=Cyclic-di-AMP hydrolase GdpP {ECO:0000303|PubMed:22956758};
DE AltName: Full=Cyclic-di-AMP phosphodiesterase YybT;
GN Name=gdpP {ECO:0000303|PubMed:22211522}; Synonyms=yybT;
GN OrderedLocusNames=BSU40510;
OS Bacillus subtilis (strain 168).
OC Bacteria; Firmicutes; Bacilli; Bacillales; Bacillaceae; Bacillus.
OX NCBI_TaxID=224308;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=168;
RX PubMed=7584024; DOI=10.1093/dnares/1.1.1;
RA Ogasawara N., Nakai S., Yoshikawa H.;
RT "Systematic sequencing of the 180 kilobase region of the Bacillus subtilis
RT chromosome containing the replication origin.";
RL DNA Res. 1:1-14(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=168;
RX PubMed=9384377; DOI=10.1038/36786;
RA Kunst F., Ogasawara N., Moszer I., Albertini A.M., Alloni G., Azevedo V.,
RA Bertero M.G., Bessieres P., Bolotin A., Borchert S., Borriss R.,
RA Boursier L., Brans A., Braun M., Brignell S.C., Bron S., Brouillet S.,
RA Bruschi C.V., Caldwell B., Capuano V., Carter N.M., Choi S.-K.,
RA Codani J.-J., Connerton I.F., Cummings N.J., Daniel R.A., Denizot F.,
RA Devine K.M., Duesterhoeft A., Ehrlich S.D., Emmerson P.T., Entian K.-D.,
RA Errington J., Fabret C., Ferrari E., Foulger D., Fritz C., Fujita M.,
RA Fujita Y., Fuma S., Galizzi A., Galleron N., Ghim S.-Y., Glaser P.,
RA Goffeau A., Golightly E.J., Grandi G., Guiseppi G., Guy B.J., Haga K.,
RA Haiech J., Harwood C.R., Henaut A., Hilbert H., Holsappel S., Hosono S.,
RA Hullo M.-F., Itaya M., Jones L.-M., Joris B., Karamata D., Kasahara Y.,
RA Klaerr-Blanchard M., Klein C., Kobayashi Y., Koetter P., Koningstein G.,
RA Krogh S., Kumano M., Kurita K., Lapidus A., Lardinois S., Lauber J.,
RA Lazarevic V., Lee S.-M., Levine A., Liu H., Masuda S., Mauel C.,
RA Medigue C., Medina N., Mellado R.P., Mizuno M., Moestl D., Nakai S.,
RA Noback M., Noone D., O'Reilly M., Ogawa K., Ogiwara A., Oudega B.,
RA Park S.-H., Parro V., Pohl T.M., Portetelle D., Porwollik S.,
RA Prescott A.M., Presecan E., Pujic P., Purnelle B., Rapoport G., Rey M.,
RA Reynolds S., Rieger M., Rivolta C., Rocha E., Roche B., Rose M., Sadaie Y.,
RA Sato T., Scanlan E., Schleich S., Schroeter R., Scoffone F., Sekiguchi J.,
RA Sekowska A., Seror S.J., Serror P., Shin B.-S., Soldo B., Sorokin A.,
RA Tacconi E., Takagi T., Takahashi H., Takemaru K., Takeuchi M.,
RA Tamakoshi A., Tanaka T., Terpstra P., Tognoni A., Tosato V., Uchiyama S.,
RA Vandenbol M., Vannier F., Vassarotti A., Viari A., Wambutt R., Wedler E.,
RA Wedler H., Weitzenegger T., Winters P., Wipat A., Yamamoto H., Yamane K.,
RA Yasumoto K., Yata K., Yoshida K., Yoshikawa H.-F., Zumstein E.,
RA Yoshikawa H., Danchin A.;
RT "The complete genome sequence of the Gram-positive bacterium Bacillus
RT subtilis.";
RL Nature 390:249-256(1997).
RN [3]
RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, ACTIVITY REGULATION,
RP BIOPHYSICOCHEMICAL PROPERTIES, DOMAIN, DISRUPTION PHENOTYPE, PROBABLE
RP TOPOLOGY, AND MUTAGENESIS OF ASP-183; GLU-225; ARG-291 AND ASP-420.
RC STRAIN=168;
RX PubMed=19901023; DOI=10.1074/jbc.m109.040238;
RA Rao F., See R.Y., Zhang D., Toh D.C., Ji Q., Liang Z.X.;
RT "YybT is a signaling protein that contains a cyclic dinucleotide
RT phosphodiesterase domain and a GGDEF domain with ATPase activity.";
RL J. Biol. Chem. 285:473-482(2010).
RN [4]
RP FUNCTION, ACTIVITY REGULATION, COFACTOR, AND DOMAIN.
RC STRAIN=168;
RX PubMed=21257773; DOI=10.1128/jb.01364-10;
RA Rao F., Ji Q., Soehano I., Liang Z.X.;
RT "Unusual heme-binding PAS domain from YybT family proteins.";
RL J. Bacteriol. 193:1543-1551(2011).
RN [5]
RP SUBCELLULAR LOCATION, DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE.
RC STRAIN=168 / PY79;
RX PubMed=21566650; DOI=10.1038/embor.2011.77;
RA Oppenheimer-Shaanan Y., Wexselblatt E., Katzhendler J., Yavin E.,
RA Ben-Yehuda S.;
RT "c-di-AMP reports DNA integrity during sporulation in Bacillus subtilis.";
RL EMBO Rep. 12:594-601(2011).
RN [6]
RP FUNCTION, DISRUPTION PHENOTYPE, AND MUTAGENESIS OF ASP-420.
RC STRAIN=168;
RX PubMed=22211522; DOI=10.1111/j.1365-2958.2011.07953.x;
RA Luo Y., Helmann J.D.;
RT "Analysis of the role of Bacillus subtilis sigma(M) in beta-lactam
RT resistance reveals an essential role for c-di-AMP in peptidoglycan
RT homeostasis.";
RL Mol. Microbiol. 83:623-639(2012).
RN [7]
RP INDUCTION.
RX PubMed=22956758; DOI=10.1099/mic.0.062174-0;
RA Luo Y., Helmann J.D.;
RT "A sigmaD-dependent antisense transcript modulates expression of the
RT cyclic-di-AMP hydrolase GdpP in Bacillus subtilis.";
RL Microbiology 158:2732-2741(2012).
RN [8]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RC STRAIN=168 / YB886 / BG214;
RX PubMed=25616256; DOI=10.1016/j.dnarep.2014.12.007;
RA Gandara C., Alonso J.C.;
RT "DisA and c-di-AMP act at the intersection between DNA-damage response and
RT stress homeostasis in exponentially growing Bacillus subtilis cells.";
RL DNA Repair 27:1-8(2015).
RN [9]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RC STRAIN=168;
RX PubMed=26240071; DOI=10.1128/jb.00564-15;
RA Gundlach J., Mehne F.M., Herzberg C., Kampf J., Valerius O., Kaever V.,
RA Stuelke J.;
RT "An essential poison: synthesis and degradation of cyclic di-AMP in
RT Bacillus subtilis.";
RL J. Bacteriol. 197:3265-3274(2015).
CC -!- FUNCTION: Has phosphodiesterase (PDE) activity against cyclic-di-AMP
CC (c-di-AMP) and to a much lesser extent against cyclic-di-GMP (c-di-GMP)
CC in the DHH/DHHA1 domains (PubMed:19901023, PubMed:21257773). Also has
CC ATPase activity, probably via the GGDEF domain (PubMed:19901023,
CC PubMed:21257773). Overexpression leads to increased sensitivity to
CC methyl methanesulfonate (MMS) and H(2)O(2) (PubMed:25616256).
CC Overexpression leads to extreme sensitivity to the beta-lactam
CC antibiotic cefuroxime (CEF), probably dependent on PDE activity
CC (PubMed:22211522). May monitor cellular heme or NO levels
CC (PubMed:21257773). In B.subtilis c-di-AMP is a second messenger that
CC mediates growth, DNA repair and cell wall homeostasis; it is toxic when
CC present in excess (PubMed:26240071). {ECO:0000269|PubMed:19901023,
CC ECO:0000269|PubMed:21257773, ECO:0000269|PubMed:22211522,
CC ECO:0000269|PubMed:25616256, ECO:0000269|PubMed:26240071}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=3',3'-c-di-AMP + H2O = 5'-O-phosphonoadenylyl-(3'->5')-
CC adenosine + H(+); Xref=Rhea:RHEA:54420, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:71500, ChEBI:CHEBI:138171;
CC EC=3.1.4.59; Evidence={ECO:0000269|PubMed:19901023};
CC -!- COFACTOR:
CC Name=heme b; Xref=ChEBI:CHEBI:60344;
CC Evidence={ECO:0000269|PubMed:21257773};
CC Note=Binds 1 heme (probably heme b) per subunit, probably hexa-
CC coordinated, which inhibits PDE and ATPase. The Fe(2+) binds CN(-), CO
CC and NO. {ECO:0000269|PubMed:21257773};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:19901023};
CC Note=ATPase activity (residues 84-303) prefers Mg(2+) over Mn(2+).
CC {ECO:0000269|PubMed:19901023};
CC -!- COFACTOR:
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000269|PubMed:19901023};
CC Note=For phosphodiesterase activity (residues 84-695), probably binds 2
CC Mn(2+) per subunit, can also use Co(2+), Mg(2+) or Ni(2+).
CC {ECO:0000269|PubMed:19901023};
CC -!- ACTIVITY REGULATION: Phosphodiesterase (PDE) inhibited by Zn(2+),
CC Ca(2+) inhibits in the presence of Mg(2+) but not Mn(2+); c-di-AMP PDE
CC activity is competitively inhibited by ppGpp (PubMed:19901023). Heme
CC binding (by Fe(2+) or Fe(3+) heme) inhibits PDE, activity is partially
CC restored by KCN or NO only for Fe(2+) heme (PubMed:21257773). Binding
CC of NO to Fe(2+) heme switches from hexa- to pentacoordination
CC (PubMed:21257773). Heme binding inhibits the ATPase activity
CC (PubMed:21257773). {ECO:0000269|PubMed:19901023,
CC ECO:0000269|PubMed:21257773}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=1.3 uM for c-di-AMP {ECO:0000269|PubMed:19901023};
CC KM=349 uM for c-di-GMP {ECO:0000269|PubMed:19901023};
CC KM=0.9 mM for ATP {ECO:0000269|PubMed:19901023};
CC Note=Phosphodiesterase kcat 0.55 for c-di-AMP, 0.23 for c-di-GMP,
CC tested for a construct expressing residues 84-695, a shorter
CC construct (residues 150-695) has a 10-fold decreased kcat for both
CC substrates. ATPase kcat 0.59. {ECO:0000269|PubMed:19901023};
CC pH dependence:
CC Optimum pH is 8.5-9.2 (for a construct expressing residues 84-695).
CC {ECO:0000269|PubMed:19901023};
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000255,
CC ECO:0000269|PubMed:21566650}; Multi-pass membrane protein
CC {ECO:0000255}. Note=After 3.5 hours of sporulation is present in a
CC punctate pattern associated with the cell membrane. Does not co-
CC localize with c-di-AMP synthase DisA. {ECO:0000269|PubMed:21566650}.
CC -!- DEVELOPMENTAL STAGE: Expressed at low levels at the onset of
CC sporulation, it rises during sporulation (at protein level).
CC {ECO:0000269|PubMed:21566650}.
CC -!- INDUCTION: Probably transcribed under control of the sigma A factor
CC (sigA), protein levels are negatively regulated by an antisense RNA
CC (PubMed:22956758). {ECO:0000269|PubMed:22956758}.
CC -!- DOMAIN: Has a GGDEF domain (residues 173-310) preceded by a PAS-like
CC domain (residues 84-149) which together have ATPase activity, followed
CC by a region with a DHH (339-496) and a DHHA1 (591-646) domain
CC (PubMed:19901023). The combined GGDEF, DHH and DHHA1 domains have c-di-
CC AMP phosphodiesterase activity (residues 150-659) that is 10-fold
CC enhanced by inclusion of the PAS-like domain (84-149); PDE activity may
CC only require the DHH/DHHA1 domains (PubMed:19901023). The PAS-like
CC domain is important for heme b-binding (PubMed:21257773).
CC {ECO:0000269|PubMed:19901023, ECO:0000269|PubMed:21257773}.
CC -!- DISRUPTION PHENOTYPE: Increased resistance to acid stress, increased
CC sporulation efficiency following DNA damage (by nalidixic acid)
CC (PubMed:19901023). Increases c-di-AMP levels in mid-exponential phase
CC from about 3.8 uM to about 4.3 uM in strain BG214 (PubMed:25616256).
CC Increased levels of c-di-AMP 4-fold during sporulation
CC (PubMed:21566650). Insertion mutations in this gene partially restore
CC antibiotic resistance to the beta-lactam antibiotic cefuroxime (CEF) in
CC a sigM deletion mutant (PubMed:22211522). Decreased sensitivity to MMS
CC and H(2)O(2) (PubMed:25616256). In strain 168 grown in minimal medium
CC and glutamate, 2.2-fold increase in c-di-AMP levels while a double
CC pgpH-gdpP mutant has 4.2-fold increased levels of in c-di-AMP; double
CC mutants die on solid medium after 2 days (PubMed:26240071).
CC {ECO:0000269|PubMed:19901023, ECO:0000269|PubMed:21566650,
CC ECO:0000269|PubMed:22211522, ECO:0000269|PubMed:25616256,
CC ECO:0000269|PubMed:26240071}.
CC -!- SIMILARITY: Belongs to the GdpP/PdeA phosphodiesterase family.
CC {ECO:0000305}.
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DR EMBL; D26185; BAA05182.1; -; Genomic_DNA.
DR EMBL; AL009126; CAB16088.1; -; Genomic_DNA.
DR PIR; S65976; S65976.
DR RefSeq; NP_391931.1; NC_000964.3.
DR RefSeq; WP_003242517.1; NZ_JNCM01000034.1.
DR AlphaFoldDB; P37484; -.
DR SMR; P37484; -.
DR STRING; 224308.BSU40510; -.
DR PaxDb; P37484; -.
DR PRIDE; P37484; -.
DR DNASU; 937816; -.
DR EnsemblBacteria; CAB16088; CAB16088; BSU_40510.
DR GeneID; 937816; -.
DR KEGG; bsu:BSU40510; -.
DR PATRIC; fig|224308.179.peg.4385; -.
DR eggNOG; COG3887; Bacteria.
DR OMA; STCELVT; -.
DR PhylomeDB; P37484; -.
DR BioCyc; BSUB:BSU40510-MON; -.
DR BRENDA; 3.1.4.59; 658.
DR Proteomes; UP000001570; Chromosome.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0106409; F:cyclic-di-AMP phosphodiesterase activity; IEA:UniProtKB-EC.
DR GO; GO:0016787; F:hydrolase activity; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0003676; F:nucleic acid binding; IEA:InterPro.
DR GO; GO:0030435; P:sporulation resulting in formation of a cellular spore; IEA:UniProtKB-KW.
DR InterPro; IPR001667; DDH_dom.
DR InterPro; IPR038763; DHH_sf.
DR InterPro; IPR003156; DHHA1_dom.
DR InterPro; IPR014528; GdpP/PdeA.
DR InterPro; IPR000160; GGDEF_dom.
DR Pfam; PF01368; DHH; 1.
DR Pfam; PF02272; DHHA1; 1.
DR PIRSF; PIRSF026583; YybT; 1.
DR SMART; SM00267; GGDEF; 1.
DR SUPFAM; SSF64182; SSF64182; 1.
DR PROSITE; PS50887; GGDEF; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Heme; Hydrolase; Iron; Manganese; Membrane; Metal-binding;
KW Reference proteome; Sporulation; Transmembrane; Transmembrane helix.
FT CHAIN 1..659
FT /note="Cyclic-di-AMP phosphodiesterase GdpP"
FT /id="PRO_0000050071"
FT TOPO_DOM 1..8
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:19901023"
FT TRANSMEM 9..29
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 30..50
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 51..659
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:19901023"
FT DOMAIN 173..301
FT /note="GGDEF"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00095"
FT REGION 84..149
FT /note="PAS-like domain, required for heme-binding"
FT /evidence="ECO:0000269|PubMed:21257773,
FT ECO:0000303|PubMed:19901023"
FT REGION 339..496
FT /note="DHH domain"
FT /evidence="ECO:0000269|PubMed:19901023"
FT REGION 591..646
FT /note="DHHA1 domain"
FT /evidence="ECO:0000269|PubMed:19901023"
FT BINDING 345
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="1"
FT /evidence="ECO:0000305|PubMed:19901023"
FT BINDING 349
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="1"
FT /evidence="ECO:0000305|PubMed:19901023"
FT BINDING 351
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="2"
FT /evidence="ECO:0000305|PubMed:19901023"
FT BINDING 420
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="1"
FT /evidence="ECO:0000305|PubMed:19901023"
FT BINDING 420
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="2"
FT /evidence="ECO:0000305|PubMed:19901023"
FT BINDING 444
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="2"
FT /evidence="ECO:0000305|PubMed:19901023"
FT BINDING 499
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="2"
FT /evidence="ECO:0000305|PubMed:19901023"
FT MUTAGEN 183
FT /note="D->A: 5% ATPase activity."
FT /evidence="ECO:0000269|PubMed:19901023"
FT MUTAGEN 225
FT /note="E->A: 5% ATPase activity."
FT /evidence="ECO:0000269|PubMed:19901023"
FT MUTAGEN 291
FT /note="R->A: 5% ATPase activity."
FT /evidence="ECO:0000269|PubMed:19901023"
FT MUTAGEN 420
FT /note="D->A: Loss of phosphodiesterase activity, does not
FT confer antibiotic sensitivity when overexpressed."
FT /evidence="ECO:0000269|PubMed:19901023,
FT ECO:0000269|PubMed:22211522"
SQ SEQUENCE 659 AA; 74325 MW; FD325C28A10EB14B CRC64;
MPSFYEKPLF RYPIYALIAL SIITILISFY FNWILGTVEV LLLAVILFFI KRADSLIRQE
IDAYISTLSY RLKKVGEEAL MEMPIGIMLF NDQYYIEWAN PFLSSCFNES TLVGRSLYDT
CESVVPLIKQ EVESETVTLN DRKFRVVIKR DERLLYFFDV TEQIQIEKLY ENERTVLAYI
FLDNYDDVTQ GLDDQTRSTM NSQVTSLLNA WAQEYGIFLK RTSSERFIAV LNEHILTELE
NSKFSILDEV REKTSFDGVA LTLSVGVGAS VSSLKELGDL AQSSLDLALG RGGDQVAIKL
PNGKVKFYGG KTNPMEKRTR VRARVISHAL KEIVTESSNV IIMGHKFPDM DSIGAAIGIL
KVAQANNKDG FIVIDPNQIG SSVQRLIGEI KKYEELWSRF ITPEEAMEIS NDDTLLVIVD
THKPSLVMEE RLVNKIEHIV VIDHHRRGEE FIRDPLLVYM EPYASSTAEL VTELLEYQPK
RLKINMIEAT ALLAGIIVDT KSFSLRTGSR TFDAASYLRA KGADTVLVQK FLKETVDSYI
KRAKLIQHTV LYKDNIAIAS LPENEEEYFD QVLIAQAADS LLSMSEVEAS FAVARRDEQT
VCISARSLGE VNVQIIMEAL EGGGHLTNAA TQLSGISVSE ALERLKHAID EYFEGGVQR
