PGPH_LISM4
ID PGPH_LISM4 Reviewed; 718 AA.
AC A0A0H3GGY3;
DT 13-APR-2016, integrated into UniProtKB/Swiss-Prot.
DT 16-SEP-2015, sequence version 1.
DT 03-AUG-2022, entry version 31.
DE RecName: Full=Cyclic-di-AMP phosphodiesterase PgpH {ECO:0000303|PubMed:25583510};
DE Short=c-di-AMP phosphodiesterase;
DE EC=3.1.4.59 {ECO:0000269|PubMed:25583510};
GN Name=pgpH {ECO:0000303|PubMed:25583510}; OrderedLocusNames=LMRG_00918;
OS Listeria monocytogenes serotype 1/2a (strain 10403S).
OC Bacteria; Firmicutes; Bacilli; Bacillales; Listeriaceae; Listeria.
OX NCBI_TaxID=393133;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=10403S;
RG The Broad Institute Genome Sequencing Platform;
RG The Broad Institute Genome Sequencing Center for Infectious Disease;
RA Borowsky M., Borodovsky M., Young S.K., Zeng Q., Koehrsen M.,
RA Fitzgerald M., Wiedmann M., Swaminathan B., Lauer P., Portnoy D.,
RA Cossart P., Buchrieser C., Higgins D., Abouelleil A., Alvarado L.,
RA Arachchi H.M., Berlin A., Borenstein D., Brown A., Chapman S.B., Chen Z.,
RA Dunbar C.D., Engels R., Freedman E., Gearin G., Gellesch M., Goldberg J.,
RA Griggs A., Gujja S., Heilman E., Heiman D., Howarth C., Jen D., Larson L.,
RA Lui A., MacDonald J., Mehta T., Montmayeur A., Neiman D., Park D.,
RA Pearson M., Priest M., Richards J., Roberts A., Saif S., Shea T.,
RA Shenoy N., Sisk P., Stolte C., Sykes S., Walk T., White J., Yandava C.,
RA Haas B., Nusbaum C., Birren B.;
RT "The genome sequence of Listeria monocytogenes strain 10403S.";
RL Submitted (APR-2010) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 494-715 IN COMPLEX WITH C-DI-AMP
RP AND MANGANESE, FUNCTION, CATALYTIC ACTIVITY, COFACTOR, ACTIVITY REGULATION,
RP DOMAIN, DISRUPTION PHENOTYPE, AND MUTAGENESIS OF HIS-543 AND ASP-544.
RC STRAIN=10403S / JW06;
RX PubMed=25583510; DOI=10.1073/pnas.1416485112;
RA Huynh T.N., Luo S., Pensinger D., Sauer J.D., Tong L., Woodward J.J.;
RT "An HD-domain phosphodiesterase mediates cooperative hydrolysis of c-di-AMP
RT to affect bacterial growth and virulence.";
RL Proc. Natl. Acad. Sci. U.S.A. 112:E747-E756(2015).
CC -!- FUNCTION: A phosphodiesterase (PDE) that hydrolyzes cyclic di-3',5'-
CC adenylate (c-di-AMP); there are at least 2 PDEs for c-di-AMP in this
CC bacteria (this and pdeA), this may be the major PDE for growth in
CC liquid culture (PubMed:25583510). During host infection c-di-AMP is
CC secreted into the host cytoplasm which leads to interferon-beta
CC production and secretion by the host (Probable). The cytoplasmic HD
CC domain binds and hydrolyzes c-di-AMP to 5'-pApA; has very low activity
CC against c-di-GMP, does not hydrolyze ppGpp (PubMed:25583510).
CC {ECO:0000269|PubMed:25583510, ECO:0000305}.
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:25583510};
CC -!- COFACTOR:
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000269|PubMed:25583510};
CC Note=Able to bind Fe(2+), but has only very weak PDE activity.
CC {ECO:0000269|PubMed:25583510};
CC -!- ACTIVITY REGULATION: c-di-AMP hydrolysis inhibited by ppGpp, without
CC altering c-di-AMP binding. {ECO:0000269|PubMed:25583510}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000255}; Multi-pass membrane
CC protein {ECO:0000255}.
CC -!- DOMAIN: The cytoplasmic domain (residues 494-718, expressed as a
CC maltose-binding protein fusion) has c-di-AMP phosphodiesterase
CC activity. {ECO:0000269|PubMed:25583510}.
CC -!- DISRUPTION PHENOTYPE: Grows as well as wild-type in culture and in
CC macrophages, double pdeA-pgpH mutants have slightly defective growth in
CC culture and in macrophages. Single mutant secretes 2-fold more c-di-
CC AMP, double mutant secretes about 4-fold more. Single mutant induces
CC wild-type interferon-beta (IFN-beta) transcription by macrophages,
CC double pdeA-pgpH mutants induces about 10-fold more IFN-beta. Double
CC mutant is 10(3)-fold less virulent in mice, suggesting increased
CC bacterial c-di-AMP is detrimental to growth within the host.
CC {ECO:0000269|PubMed:25583510}.
CC -!- SIMILARITY: Belongs to the PgpH phosphodiesterase family.
CC {ECO:0000305}.
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DR EMBL; CP002002; AEO06451.1; -; Genomic_DNA.
DR RefSeq; WP_003721972.1; NC_017544.1.
DR PDB; 4S1B; X-ray; 2.10 A; A/D=494-715.
DR PDB; 4S1C; X-ray; 2.40 A; A/D=494-715.
DR PDBsum; 4S1B; -.
DR PDBsum; 4S1C; -.
DR AlphaFoldDB; A0A0H3GGY3; -.
DR SMR; A0A0H3GGY3; -.
DR EnsemblBacteria; AEO06451; AEO06451; LMRG_00918.
DR KEGG; lmt:LMRG_00918; -.
DR HOGENOM; CLU_015767_1_2_9; -.
DR OMA; DFIRTHH; -.
DR Proteomes; UP000001288; Chromosome.
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:0000166; F:nucleotide binding; IEA:UniProtKB-KW.
DR CDD; cd00077; HDc; 1.
DR InterPro; IPR003607; HD/PDEase_dom.
DR InterPro; IPR006674; HD_domain.
DR InterPro; IPR006675; HDIG_dom.
DR InterPro; IPR011624; Metal-dep_PHydrolase_7TM_extra.
DR InterPro; IPR011621; Metal-dep_PHydrolase_7TM_intra.
DR Pfam; PF07698; 7TM-7TMR_HD; 1.
DR Pfam; PF07697; 7TMR-HDED; 1.
DR Pfam; PF01966; HD; 1.
DR SMART; SM00471; HDc; 1.
DR TIGRFAMs; TIGR00277; HDIG; 1.
DR PROSITE; PS51831; HD; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Hydrolase; Manganese; Membrane; Metal-binding;
KW Nucleotide-binding; Transmembrane; Transmembrane helix.
FT CHAIN 1..718
FT /note="Cyclic-di-AMP phosphodiesterase PgpH"
FT /id="PRO_0000436054"
FT TOPO_DOM 1..17
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 18..38
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 39..289
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 290..310
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 311..324
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 325..345
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 346..349
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 350..370
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 371..391
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 392
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 393..413
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 414..421
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 422..442
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 443..457
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 458..478
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 479..718
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT DOMAIN 511..653
FT /note="HD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01175"
FT REGION 112..140
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 514
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="1"
FT /evidence="ECO:0000305|PubMed:25583510"
FT BINDING 514
FT /ligand="substrate"
FT /evidence="ECO:0000305|PubMed:25583510"
FT BINDING 543
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="1"
FT /evidence="ECO:0000305|PubMed:25583510"
FT BINDING 544..547
FT /ligand="substrate"
FT /evidence="ECO:0000305|PubMed:25583510"
FT BINDING 544
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="1"
FT /evidence="ECO:0000305|PubMed:25583510"
FT BINDING 544
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="2"
FT /evidence="ECO:0000305|PubMed:25583510"
FT BINDING 555..556
FT /ligand="substrate"
FT /evidence="ECO:0000305|PubMed:25583510"
FT BINDING 580
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="2"
FT /evidence="ECO:0000305|PubMed:25583510"
FT BINDING 604
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="2"
FT /evidence="ECO:0000305|PubMed:25583510"
FT BINDING 605
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="2"
FT /evidence="ECO:0000305|PubMed:25583510"
FT BINDING 631
FT /ligand="substrate"
FT /evidence="ECO:0000305|PubMed:25583510"
FT BINDING 648
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="1"
FT /evidence="ECO:0000305|PubMed:25583510"
FT BINDING 648
FT /ligand="substrate"
FT /evidence="ECO:0000305|PubMed:25583510"
FT MUTAGEN 543
FT /note="H->A: Decreased Mn(2+) binding, decreased c-di-AMP
FT binding, no c-di-AMP hydrolysis."
FT /evidence="ECO:0000269|PubMed:25583510"
FT MUTAGEN 544
FT /note="D->A: Loss of Mn(2+) binding, considerably decreased
FT c-di-AMP binding, no c-di-AMP hydrolysis."
FT /evidence="ECO:0000269|PubMed:25583510"
SQ SEQUENCE 718 AA; 81112 MW; 139C2855168FB1C7 CRC64;
MKLAKKWRDW YIESGKKYLF PLLLVCFAVI AYFLVCQMTK PESYNVKLFQ VAEKTIRSPQ
TVEDTEKTKE ERTKASDAVE DVYVYNRETG QNRVALIQSL FAYVNEVNAE AQEKDTKNKE
KAKKENKPAP APTSTEDKLK NLKDKLSSNV SEKITSNISD EVFTTLIEAK SKDFNVMEDV
VTTEVEKSME NKIRDENLNS VKIRARDDIE LSAIPAYYKN VSKALVSYAI VPNEVYDEEQ
TDARRKEAAQ SVVPVKILQG QVIVQEGQIV DRETYRQLKM LHLLDQKMPV KQYAGFAIFI
IALAAILFLY TKKQTQPKAK KMQTMLIFSS VYLVSLFMLF IILFLETQNI ANIAFLFPAA
FAPMILKILL NEKYAFLSVI FIAVTSLLTF QNDATSGITI FILLSGATSV VMLRDYSRRS
AIMLSGFMVG LINMIYVLLL LLINNSTLLQ VSTLMALGYA FLGGFGAFIL GVGVIPLFET
IFGLLTTSRL VELANPNHPL LKKILMKAPG TYHHSMMVAN LAEACADKIG ANSLLVRVGC
FYHDIGKTLR PPYFVENQLQ GINPHDRLTP EQSRDIILSH TKDGAEILKE NHMPQPIIDI
ALQHHGTTLL KYFYFKAKET NPDVKEADYR YSGPKPQTKE IAIINISDSV EAAVRSSTEP
TMAKITEIID GIIKDRFLDG QFTECDITIQ EIKIIRDTLI ATLNGIYHQR IQYPDDKD
