DISA_THEMA
ID DISA_THEMA Reviewed; 357 AA.
AC Q9WY43;
DT 31-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 03-AUG-2022, entry version 127.
DE RecName: Full=DNA integrity scanning protein DisA {ECO:0000255|HAMAP-Rule:MF_01438};
DE AltName: Full=Cyclic di-AMP synthase {ECO:0000255|HAMAP-Rule:MF_01438};
DE Short=c-di-AMP synthase {ECO:0000255|HAMAP-Rule:MF_01438};
DE AltName: Full=Diadenylate cyclase {ECO:0000255|HAMAP-Rule:MF_01438};
DE EC=2.7.7.85 {ECO:0000255|HAMAP-Rule:MF_01438, ECO:0000269|PubMed:18439896};
GN Name=disA {ECO:0000255|HAMAP-Rule:MF_01438}; OrderedLocusNames=TM_0200;
OS Thermotoga maritima (strain ATCC 43589 / DSM 3109 / JCM 10099 / NBRC 100826
OS / MSB8).
OC Bacteria; Thermotogae; Thermotogales; Thermotogaceae; Thermotoga.
OX NCBI_TaxID=243274;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 43589 / DSM 3109 / JCM 10099 / NBRC 100826 / MSB8;
RX PubMed=10360571; DOI=10.1038/20601;
RA Nelson K.E., Clayton R.A., Gill S.R., Gwinn M.L., Dodson R.J., Haft D.H.,
RA Hickey E.K., Peterson J.D., Nelson W.C., Ketchum K.A., McDonald L.A.,
RA Utterback T.R., Malek J.A., Linher K.D., Garrett M.M., Stewart A.M.,
RA Cotton M.D., Pratt M.S., Phillips C.A., Richardson D.L., Heidelberg J.F.,
RA Sutton G.G., Fleischmann R.D., Eisen J.A., White O., Salzberg S.L.,
RA Smith H.O., Venter J.C., Fraser C.M.;
RT "Evidence for lateral gene transfer between Archaea and Bacteria from
RT genome sequence of Thermotoga maritima.";
RL Nature 399:323-329(1999).
RN [2]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF APOPROTEIN AND IN COMPLEXES WITH
RP ATP ANALOGS OR PRODUCT C-DI-AMP, FUNCTION, CATALYTIC ACTIVITY, SUBSTRATE
RP SPECIFICITY, SUBUNIT, AND DOMAIN.
RX PubMed=18439896; DOI=10.1016/j.molcel.2008.02.020;
RA Witte G., Hartung S., Buttner K., Hopfner K.P.;
RT "Structural biochemistry of a bacterial checkpoint protein reveals
RT diadenylate cyclase activity regulated by DNA recombination
RT intermediates.";
RL Mol. Cell 30:167-178(2008).
RN [3]
RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) IN COMPLEX WITH PRODUCT C-DI-AMP OR
RP ATP ANALOGS AND METAL, FUNCTION, COFACTOR, ACTIVITY REGULATION, SUBUNIT,
RP DOMAIN, AND MUTAGENESIS OF ASP-75; 107-THR--THR-111; 108-ARG--ARG-110;
RP 128-ARG--ARG-130 AND ARG-130.
RX PubMed=26014055; DOI=10.1042/bj20150373;
RA Muller M., Deimling T., Hopfner K.P., Witte G.;
RT "Structural analysis of the diadenylate cyclase reaction of DNA-integrity
RT scanning protein A (DisA) and its inhibition by 3'-dATP.";
RL Biochem. J. 469:367-374(2015).
CC -!- FUNCTION: Participates in a DNA-damage check-point. DisA forms globular
CC foci that rapidly scan along the chromosomes searching for lesions.
CC {ECO:0000255|HAMAP-Rule:MF_01438}.
CC -!- FUNCTION: Has diadenylate cyclase activity, catalyzing the condensation
CC of 2 ATP molecules into cyclic di-AMP (c-di-AMP) (PubMed:18439896,
CC PubMed:26014055). c-di-AMP likely acts as a signaling molecule that may
CC couple DNA integrity with a cellular process. This rate-limiting step
CC is the accessibility of the active site; mutating the possible exit
CC tunnel (residues 128-130) increases product 2-fold despite Arg-130
CC being important for ATP-binding (PubMed:26014055). Does not convert GTP
CC to c-di-GMP (PubMed:18439896). {ECO:0000255|HAMAP-Rule:MF_01438,
CC ECO:0000269|PubMed:18439896, ECO:0000269|PubMed:26014055}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 ATP = 3',3'-c-di-AMP + 2 diphosphate; Xref=Rhea:RHEA:35655,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:71500; EC=2.7.7.85;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_01438,
CC ECO:0000269|PubMed:18439896};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_01438,
CC ECO:0000305|PubMed:26014055};
CC Note=Crystallized with Mn(2+) to trap in the pre-reaction state.
CC {ECO:0000269|PubMed:26014055};
CC -!- ACTIVITY REGULATION: Inhibited by 3'-dATP.
CC {ECO:0000269|PubMed:26014055}.
CC -!- SUBUNIT: Homooctamer. {ECO:0000255|HAMAP-Rule:MF_01438,
CC ECO:0000269|PubMed:18439896, ECO:0000269|PubMed:26014055}.
CC -!- DOMAIN: Consists of three domains: an N-terminal globular domain with
CC diadenylate-cyclase (DAC) activity, a central helical domain and a C-
CC terminal DNA-binding domain. {ECO:0000269|PubMed:18439896,
CC ECO:0000269|PubMed:26014055}.
CC -!- SIMILARITY: Belongs to the DisA family. {ECO:0000255|HAMAP-
CC Rule:MF_01438}.
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DR EMBL; AE000512; AAD35292.1; -; Genomic_DNA.
DR PIR; B72405; B72405.
DR RefSeq; NP_228015.1; NC_000853.1.
DR PDB; 3C1Y; X-ray; 2.10 A; A/B=1-357.
DR PDB; 3C1Z; X-ray; 2.30 A; A/B=1-357.
DR PDB; 3C21; X-ray; 2.70 A; A/B=1-357.
DR PDB; 3C23; X-ray; 2.50 A; A/B=1-357.
DR PDB; 4YVZ; X-ray; 2.50 A; A/B=1-357.
DR PDB; 4YXJ; X-ray; 2.55 A; A/B=1-357.
DR PDB; 4YXM; X-ray; 2.25 A; A/B=1-357.
DR PDBsum; 3C1Y; -.
DR PDBsum; 3C1Z; -.
DR PDBsum; 3C21; -.
DR PDBsum; 3C23; -.
DR PDBsum; 4YVZ; -.
DR PDBsum; 4YXJ; -.
DR PDBsum; 4YXM; -.
DR AlphaFoldDB; Q9WY43; -.
DR SMR; Q9WY43; -.
DR STRING; 243274.THEMA_03730; -.
DR EnsemblBacteria; AAD35292; AAD35292; TM_0200.
DR KEGG; tma:TM0200; -.
DR PATRIC; fig|243274.5.peg.202; -.
DR eggNOG; COG1623; Bacteria.
DR InParanoid; Q9WY43; -.
DR OMA; VVRDYVP; -.
DR BRENDA; 2.7.7.85; 6331.
DR EvolutionaryTrace; Q9WY43; -.
DR Proteomes; UP000008183; Chromosome.
DR GO; GO:0004016; F:adenylate cyclase activity; IBA:GO_Central.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-UniRule.
DR GO; GO:0106408; F:diadenylate cyclase activity; IEA:UniProtKB-EC.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-UniRule.
DR GO; GO:0006281; P:DNA repair; IEA:UniProtKB-UniRule.
DR GO; GO:0019932; P:second-messenger-mediated signaling; IEA:UniProtKB-UniRule.
DR Gene3D; 1.20.1260.110; -; 1.
DR Gene3D; 3.40.1700.10; -; 1.
DR HAMAP; MF_01438; DisA; 1.
DR InterPro; IPR038331; DisA_sf.
DR InterPro; IPR036888; DNA_integrity_DisA_N_sf.
DR InterPro; IPR018906; DNA_integrity_scan_DisA_link.
DR InterPro; IPR003390; DNA_integrity_scan_DisA_N.
DR InterPro; IPR023763; DNA_integrity_scanning_protein.
DR InterPro; IPR000445; HhH_motif.
DR InterPro; IPR010994; RuvA_2-like.
DR Pfam; PF02457; DAC; 1.
DR Pfam; PF10635; DisA-linker; 1.
DR Pfam; PF00633; HHH; 1.
DR SUPFAM; SSF143597; SSF143597; 1.
DR SUPFAM; SSF47781; SSF47781; 1.
DR PROSITE; PS51794; DAC; 1.
PE 1: Evidence at protein level;
KW 3D-structure; ATP-binding; DNA damage; DNA repair; DNA-binding; Magnesium;
KW Nucleotide-binding; Nucleotidyltransferase; Reference proteome;
KW Transferase.
FT CHAIN 1..357
FT /note="DNA integrity scanning protein DisA"
FT /id="PRO_0000255653"
FT DOMAIN 8..148
FT /note="DAC"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01130"
FT BINDING 76
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:18439896,
FT ECO:0000269|PubMed:26014055"
FT BINDING 94
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:18439896,
FT ECO:0000269|PubMed:26014055"
FT BINDING 107..111
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:18439896,
FT ECO:0000269|PubMed:26014055"
FT BINDING 127..130
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:18439896,
FT ECO:0000269|PubMed:26014055"
FT MUTAGEN 75
FT /note="D->N: Significant loss of c-di-AMP formation, still
FT forms octamers."
FT /evidence="ECO:0000269|PubMed:26014055"
FT MUTAGEN 107..111
FT /note="TRHRT->VRHRV: Significant loss of c-di-AMP
FT formation."
FT /evidence="ECO:0000269|PubMed:26014055"
FT MUTAGEN 108..110
FT /note="RHR->AAA: About 90% loss of c-di-AMP formation."
FT /evidence="ECO:0000269|PubMed:26014055"
FT MUTAGEN 128..130
FT /note="RRR->AAA: 2-fold increase in c-di-AMP formation."
FT /evidence="ECO:0000269|PubMed:26014055"
FT MUTAGEN 130
FT /note="R->A: About 90% loss of c-di-AMP formation."
FT /evidence="ECO:0000269|PubMed:26014055"
FT HELIX 9..15
FT /evidence="ECO:0007829|PDB:3C1Y"
FT HELIX 16..18
FT /evidence="ECO:0007829|PDB:3C1Y"
FT HELIX 23..33
FT /evidence="ECO:0007829|PDB:3C1Y"
FT STRAND 38..42
FT /evidence="ECO:0007829|PDB:3C1Y"
FT HELIX 46..49
FT /evidence="ECO:0007829|PDB:3C1Y"
FT TURN 50..52
FT /evidence="ECO:0007829|PDB:3C1Y"
FT STRAND 53..62
FT /evidence="ECO:0007829|PDB:3C1Y"
FT HELIX 65..71
FT /evidence="ECO:0007829|PDB:3C1Y"
FT STRAND 74..80
FT /evidence="ECO:0007829|PDB:3C1Y"
FT STRAND 84..94
FT /evidence="ECO:0007829|PDB:3C1Y"
FT HELIX 107..119
FT /evidence="ECO:0007829|PDB:3C1Y"
FT STRAND 120..126
FT /evidence="ECO:0007829|PDB:3C1Y"
FT STRAND 128..131
FT /evidence="ECO:0007829|PDB:3C1Z"
FT STRAND 133..136
FT /evidence="ECO:0007829|PDB:3C1Y"
FT STRAND 141..144
FT /evidence="ECO:0007829|PDB:3C1Y"
FT HELIX 147..180
FT /evidence="ECO:0007829|PDB:3C1Y"
FT HELIX 186..212
FT /evidence="ECO:0007829|PDB:3C1Y"
FT HELIX 214..217
FT /evidence="ECO:0007829|PDB:3C1Y"
FT HELIX 218..228
FT /evidence="ECO:0007829|PDB:3C1Y"
FT HELIX 231..242
FT /evidence="ECO:0007829|PDB:3C1Y"
FT STRAND 243..245
FT /evidence="ECO:0007829|PDB:3C1Y"
FT HELIX 249..260
FT /evidence="ECO:0007829|PDB:3C1Y"
FT STRAND 261..263
FT /evidence="ECO:0007829|PDB:3C23"
FT HELIX 267..273
FT /evidence="ECO:0007829|PDB:3C1Y"
FT HELIX 281..286
FT /evidence="ECO:0007829|PDB:3C1Y"
FT HELIX 294..299
FT /evidence="ECO:0007829|PDB:3C1Y"
FT HELIX 305..315
FT /evidence="ECO:0007829|PDB:3C1Y"
FT HELIX 318..321
FT /evidence="ECO:0007829|PDB:3C1Y"
FT HELIX 326..329
FT /evidence="ECO:0007829|PDB:3C1Y"
FT HELIX 337..354
FT /evidence="ECO:0007829|PDB:3C1Y"
SQ SEQUENCE 357 AA; 40540 MW; 45C1318A21F315A9 CRC64;
MGVKSLVPQE LIEKIKLISP GTELRKALDD IINANFGALI FLVDDPKKYE DVIQGGFWLD
TDFSAEKLYE LSKMDGAIVL SEDITKIYYA NVHLVPDPTI PTGETGTRHR TAERLAKQTG
KVVIAVSRRR NIISLYYKNY KYVVNQVDFL ISKVTQAIST LEKYKDNFNK LLSELEVLEL
ENRVTLADVV RTLAKGFELL RIVEEIRPYI VELGEEGRLA RMQLRELTED VDDLLVLLIM
DYSSEEVEEE TAQNILQDFI TRREPSPISI SRVLGYDVQQ AAQLDDVLVS ARGYRLLKTV
ARIPLSIGYN VVRMFKTLDQ ISKASVEDLK KVEGIGEKRA RAISESISSL KHRKTSE
