CIF_BURPS
ID CIF_BURPS Reviewed; 328 AA.
AC Q63KH5;
DT 29-SEP-2021, integrated into UniProtKB/Swiss-Prot.
DT 25-OCT-2004, sequence version 1.
DT 03-AUG-2022, entry version 81.
DE RecName: Full=Protein-glutamine deamidase Cif {ECO:0000305};
DE EC=3.5.1.44 {ECO:0000269|PubMed:20688984};
DE AltName: Full=Cycle-inhibiting factor homolog {ECO:0000303|PubMed:19308257};
DE Short=CHBP {ECO:0000303|PubMed:19225106, ECO:0000303|PubMed:20688984};
GN Name=cif {ECO:0000303|PubMed:19308257};
GN OrderedLocusNames=BPSS1385 {ECO:0000312|EMBL:CAH38859.1};
OS Burkholderia pseudomallei (strain K96243).
OC Bacteria; Proteobacteria; Betaproteobacteria; Burkholderiales;
OC Burkholderiaceae; Burkholderia; pseudomallei group.
OX NCBI_TaxID=272560;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=K96243;
RX PubMed=15377794; DOI=10.1073/pnas.0403302101;
RA Holden M.T.G., Titball R.W., Peacock S.J., Cerdeno-Tarraga A.-M.,
RA Atkins T., Crossman L.C., Pitt T., Churcher C., Mungall K.L., Bentley S.D.,
RA Sebaihia M., Thomson N.R., Bason N., Beacham I.R., Brooks K., Brown K.A.,
RA Brown N.F., Challis G.L., Cherevach I., Chillingworth T., Cronin A.,
RA Crossett B., Davis P., DeShazer D., Feltwell T., Fraser A., Hance Z.,
RA Hauser H., Holroyd S., Jagels K., Keith K.E., Maddison M., Moule S.,
RA Price C., Quail M.A., Rabbinowitsch E., Rutherford K., Sanders M.,
RA Simmonds M., Songsivilai S., Stevens K., Tumapa S., Vesaratchavest M.,
RA Whitehead S., Yeats C., Barrell B.G., Oyston P.C.F., Parkhill J.;
RT "Genomic plasticity of the causative agent of melioidosis, Burkholderia
RT pseudomallei.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:14240-14245(2004).
RN [2]
RP FUNCTION, ACTIVE SITE, SUBCELLULAR LOCATION, AND MUTAGENESIS OF CYS-156.
RX PubMed=19308257; DOI=10.1371/journal.pone.0004855;
RA Jubelin G., Chavez C.V., Taieb F., Banfield M.J., Samba-Louaka A., Nobe R.,
RA Nougayrede J.P., Zumbihl R., Givaudan A., Escoubas J.M., Oswald E.;
RT "Cycle inhibiting factors (CIFs) are a growing family of functional
RT cyclomodulins present in invertebrate and mammal bacterial pathogens.";
RL PLoS ONE 4:e4855-e4855(2009).
RN [3]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, SUBCELLULAR LOCATION, AND
RP MUTAGENESIS OF CYS-156.
RX PubMed=20688984; DOI=10.1126/science.1193844;
RA Cui J., Yao Q., Li S., Ding X., Lu Q., Mao H., Liu L., Zheng N., Chen S.,
RA Shao F.;
RT "Glutamine deamidation and dysfunction of ubiquitin/NEDD8 induced by a
RT bacterial effector family.";
RL Science 329:1215-1218(2010).
RN [4]
RP FUNCTION.
RX PubMed=21903097; DOI=10.1016/j.jmb.2011.08.030;
RA Boh B.K., Ng M.Y., Leck Y.C., Shaw B., Long J., Sun G.W., Gan Y.H.,
RA Searle M.S., Layfield R., Hagen T.;
RT "Inhibition of cullin RING ligases by cycle inhibiting factor: evidence for
RT interference with Nedd8-induced conformational control.";
RL J. Mol. Biol. 413:430-437(2011).
RN [5]
RP FUNCTION, AND MUTAGENESIS OF CYS-156.
RX PubMed=28166272; DOI=10.1371/journal.pone.0171464;
RA Ng M.Y., Wang M., Casey P.J., Gan Y.H., Hagen T.;
RT "Activation of MAPK/ERK signaling by Burkholderia pseudomallei cycle
RT inhibiting factor (Cif).";
RL PLoS ONE 12:e0171464-e0171464(2017).
RN [6]
RP FUNCTION, AND MUTAGENESIS OF CYS-156.
RX PubMed=29848489; DOI=10.1242/bio.028225;
RA Ng M.Y., Gan Y.H., Hagen T.;
RT "Characterisation of cellular effects of Burkholderia pseudomallei cycle
RT inhibiting factor (Cif).";
RL Biol. Open 7:0-0(2018).
RN [7] {ECO:0007744|PDB:3GQM}
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 67-328, AND ACTIVE SITE.
RX PubMed=19440549; DOI=10.1371/journal.pone.0005582;
RA Crow A., Race P.R., Jubelin G., Varela Chavez C., Escoubas J.M., Oswald E.,
RA Banfield M.J.;
RT "Crystal structures of Cif from bacterial pathogens Photorhabdus
RT luminescens and Burkholderia pseudomallei.";
RL PLoS ONE 4:e5582-e5582(2009).
RN [8] {ECO:0007744|PDB:3EIR, ECO:0007744|PDB:3EIT}
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 48-328, FUNCTION, ACTIVE SITES,
RP AND MUTAGENESIS OF CYS-156; HIS-211 AND GLN-231.
RX PubMed=19225106; DOI=10.1073/pnas.0900212106;
RA Yao Q., Cui J., Zhu Y., Wang G., Hu L., Long C., Cao R., Liu X., Huang N.,
RA Chen S., Liu L., Shao F.;
RT "A bacterial type III effector family uses the papain-like hydrolytic
RT activity to arrest the host cell cycle.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:3716-3721(2009).
RN [9] {ECO:0007744|PDB:4HCN, ECO:0007744|PDB:4HCP}
RP X-RAY CRYSTALLOGRAPHY (2.52 ANGSTROMS) OF 78-328 IN COMPLEX WITH HOST
RP UBIQUITIN AND NEDD8, FUNCTION, AND MUTAGENESIS OF 107-ASN-ASP-108;
RP 133-PHE--LEU-142; ASN-161 AND THR-177.
RX PubMed=23175788; DOI=10.1073/pnas.1210831109;
RA Yao Q., Cui J., Wang J., Li T., Wan X., Luo T., Gong Y.N., Xu Y., Huang N.,
RA Shao F.;
RT "Structural mechanism of ubiquitin and NEDD8 deamidation catalyzed by
RT bacterial effectors that induce macrophage-specific apoptosis.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:20395-20400(2012).
CC -!- FUNCTION: Protein-glutamine deamidase effector that inhibits the host
CC cell cycle and other key cellular processes such as the actin network
CC and programmed-cell death (PubMed:19308257, PubMed:20688984,
CC PubMed:19225106). Acts by mediating the side chain deamidation of 'Gln-
CC 40' of host NEDD8, converting it to glutamate, thereby abolishing the
CC activity of cullin-RING-based E3 ubiquitin-protein ligase complexes
CC (CRL complexes) (PubMed:20688984, PubMed:21903097). Inactivation of CRL
CC complexes prevents ubiquitination and subsequent degradation of the
CC cyclin-dependent kinase inhibitors CDKN1A/p21 and CDKN1B/p27, leading
CC to G1 and G2 cell cycle arrests in host cells (PubMed:19308257).
CC Deamidation of 'Gln-40' of host NEDD8 also triggers macrophage-specific
CC programmed cell death (PubMed:23175788). Also able to catalyze
CC deamidation of 'Gln-40' of host ubiquitin in vitro; however, NEDD8
CC constitutes the preferred substrate in vivo (PubMed:20688984). Also
CC regulates the host NF-kappa-B signaling via activation of MAPK/ERK
CC cascade: activation of host MAPK/ERK cascade is independent of CRL
CC complexes inhibition, suggesting that Cif has other host protein
CC targets than NEDD8 (PubMed:28166272, PubMed:29848489).
CC {ECO:0000269|PubMed:19225106, ECO:0000269|PubMed:19308257,
CC ECO:0000269|PubMed:20688984, ECO:0000269|PubMed:21903097,
CC ECO:0000269|PubMed:23175788, ECO:0000269|PubMed:28166272,
CC ECO:0000269|PubMed:29848489}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + L-glutaminyl-[protein] = L-glutamyl-[protein] + NH4(+);
CC Xref=Rhea:RHEA:16441, Rhea:RHEA-COMP:10207, Rhea:RHEA-COMP:10208,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:28938, ChEBI:CHEBI:29973,
CC ChEBI:CHEBI:30011; EC=3.5.1.44;
CC Evidence={ECO:0000269|PubMed:20688984};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16442;
CC Evidence={ECO:0000269|PubMed:20688984};
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:19308257,
CC ECO:0000269|PubMed:20688984}. Host nucleus
CC {ECO:0000250|UniProtKB:P0DUW5}. Note=Secreted via the type III
CC secretion system (TTSS). {ECO:0000269|PubMed:19308257,
CC ECO:0000269|PubMed:20688984}.
CC -!- SIMILARITY: Belongs to the Cif family. {ECO:0000305}.
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DR EMBL; BX571966; CAH38859.1; -; Genomic_DNA.
DR RefSeq; WP_009934508.1; NZ_CP009537.1.
DR RefSeq; YP_111397.1; NC_006351.1.
DR PDB; 3EIR; X-ray; 2.10 A; A/B=48-328.
DR PDB; 3EIT; X-ray; 2.56 A; A/B=48-328.
DR PDB; 3GQM; X-ray; 2.10 A; A/B=67-328.
DR PDB; 4HCN; X-ray; 2.60 A; A=78-328.
DR PDB; 4HCP; X-ray; 2.52 A; A=78-328.
DR PDBsum; 3EIR; -.
DR PDBsum; 3EIT; -.
DR PDBsum; 3GQM; -.
DR PDBsum; 4HCN; -.
DR PDBsum; 4HCP; -.
DR SMR; Q63KH5; -.
DR STRING; 272560.BPSS1385; -.
DR EnsemblBacteria; CAH38859; CAH38859; BPSS1385.
DR KEGG; bps:BPSS1385; -.
DR PATRIC; fig|272560.6.peg.5616; -.
DR eggNOG; ENOG5032RCC; Bacteria.
DR OMA; RFEDWMT; -.
DR EvolutionaryTrace; Q63KH5; -.
DR PHI-base; PHI:4195; -.
DR Proteomes; UP000000605; Chromosome 2.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0042025; C:host cell nucleus; ISS:UniProtKB.
DR GO; GO:0050568; F:protein-glutamine glutaminase activity; IDA:UniProtKB.
DR GO; GO:0090729; F:toxin activity; IDA:UniProtKB.
DR GO; GO:0075131; P:induction by symbiont of host protein kinase-mediated signal transduction; IDA:UniProtKB.
DR GO; GO:0044071; P:modulation by symbiont of host cell cycle; IDA:UniProtKB.
DR InterPro; IPR032278; Cif.
DR Pfam; PF16374; CIF; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Host nucleus; Hydrolase; Reference proteome; Secreted; Toxin;
KW Virulence.
FT CHAIN 1..328
FT /note="Protein-glutamine deamidase Cif"
FT /id="PRO_0000453901"
FT REGION 1..68
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 51..68
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 156
FT /evidence="ECO:0000305|PubMed:19225106,
FT ECO:0000305|PubMed:19308257, ECO:0000305|PubMed:19440549,
FT ECO:0000305|PubMed:20688984"
FT ACT_SITE 211
FT /evidence="ECO:0000305|PubMed:19225106,
FT ECO:0000305|PubMed:19440549"
FT ACT_SITE 231
FT /evidence="ECO:0000305|PubMed:19225106,
FT ECO:0000305|PubMed:19440549"
FT MUTAGEN 107..108
FT /note="ND->AA: Impaired ability to mediate deamidation of
FT host NEDD8, leading to decreased ability to inhibit the
FT host cell cycle."
FT /evidence="ECO:0000269|PubMed:23175788"
FT MUTAGEN 133..142
FT /note="FGGLENYKEL->AGGLENAKEA: Impaired ability to mediate
FT deamidation of host NEDD8, leading to decreased ability to
FT inhibit the host cell cycle."
FT /evidence="ECO:0000269|PubMed:23175788"
FT MUTAGEN 156
FT /note="C->S: Abolished protein-glutamine deamidase
FT activity, leading to impaired ability to inhibit the host
FT cell cycle. Abolished accumulation of the cyclin-dependent
FT kinase inhibitors CDKN1A/p21 and CDKN1B/p27. Abolished
FT ability to activate the host MAPK/ERK cascade."
FT /evidence="ECO:0000269|PubMed:19225106,
FT ECO:0000269|PubMed:19308257, ECO:0000269|PubMed:20688984,
FT ECO:0000269|PubMed:28166272, ECO:0000269|PubMed:29848489"
FT MUTAGEN 161
FT /note="N->A: Impaired ability to mediate deamidation of
FT host NEDD8, leading to decreased ability to inhibit the
FT host cell cycle; when associated with A-177."
FT /evidence="ECO:0000269|PubMed:23175788"
FT MUTAGEN 177
FT /note="T->A: Impaired ability to mediate deamidation of
FT host NEDD8, leading to decreased ability to inhibit the
FT host cell cycle; when associated with A-161."
FT /evidence="ECO:0000269|PubMed:23175788"
FT MUTAGEN 211
FT /note="H->N: Abolished ability to inhibit the host cell
FT cycle."
FT /evidence="ECO:0000269|PubMed:19225106"
FT MUTAGEN 231
FT /note="Q->A: Abolished ability to inhibit the host cell
FT cycle."
FT /evidence="ECO:0000269|PubMed:19225106"
FT HELIX 81..94
FT /evidence="ECO:0007829|PDB:3GQM"
FT HELIX 95..97
FT /evidence="ECO:0007829|PDB:3GQM"
FT HELIX 99..105
FT /evidence="ECO:0007829|PDB:3GQM"
FT HELIX 114..116
FT /evidence="ECO:0007829|PDB:3GQM"
FT HELIX 119..132
FT /evidence="ECO:0007829|PDB:3GQM"
FT HELIX 136..142
FT /evidence="ECO:0007829|PDB:3GQM"
FT HELIX 156..168
FT /evidence="ECO:0007829|PDB:3GQM"
FT STRAND 170..172
FT /evidence="ECO:0007829|PDB:3GQM"
FT TURN 176..178
FT /evidence="ECO:0007829|PDB:3GQM"
FT STRAND 182..184
FT /evidence="ECO:0007829|PDB:3GQM"
FT HELIX 187..191
FT /evidence="ECO:0007829|PDB:3GQM"
FT STRAND 198..206
FT /evidence="ECO:0007829|PDB:3GQM"
FT TURN 207..210
FT /evidence="ECO:0007829|PDB:3GQM"
FT STRAND 211..217
FT /evidence="ECO:0007829|PDB:3GQM"
FT STRAND 227..230
FT /evidence="ECO:0007829|PDB:3GQM"
FT STRAND 236..239
FT /evidence="ECO:0007829|PDB:3GQM"
FT HELIX 244..251
FT /evidence="ECO:0007829|PDB:3GQM"
FT HELIX 258..264
FT /evidence="ECO:0007829|PDB:3GQM"
FT HELIX 267..271
FT /evidence="ECO:0007829|PDB:3GQM"
FT HELIX 274..285
FT /evidence="ECO:0007829|PDB:3GQM"
FT HELIX 291..293
FT /evidence="ECO:0007829|PDB:3GQM"
FT HELIX 296..298
FT /evidence="ECO:0007829|PDB:3GQM"
FT STRAND 305..312
FT /evidence="ECO:0007829|PDB:3GQM"
FT HELIX 314..325
FT /evidence="ECO:0007829|PDB:3GQM"
SQ SEQUENCE 328 AA; 35819 MW; 26F47A17DBE7370F CRC64;
MLEHGVMKIP GINNVGKTGQ AGGETERIPS TEPLGSSAAT SPAGPLGGLP ARSSSISNTN
RTGENPMITP IISSNLGLKH RVTLRKATLA SLMQSLSGES SNRVMWNDRY DTLLIARDPR
EIKNAIEKSV TDFGGLENYK ELTGGADPFA LMTPVCGLSA NNIFKLMTEK DVPIDPTSIE
YLENTSFAEH VNTLDSHKNY VVIVNDGRLG HKFLIDLPAL TQGPRTAYII QSDLGGGALP
AVRVEDWISR RGSDPVSLDE LNQLLSKDFS KMPDDVQTRL LASILQIDKD PHKVDIKKLH
LDGKLRFASH EYDFRQFQRN AQYVAGLG
