CIF_ECOLX
ID CIF_ECOLX Reviewed; 282 AA.
AC P0DUW5;
DT 29-SEP-2021, integrated into UniProtKB/Swiss-Prot.
DT 29-SEP-2021, sequence version 1.
DT 25-MAY-2022, entry version 3.
DE RecName: Full=Protein-glutamine deamidase Cif;
DE EC=3.5.1.44 {ECO:0000269|PubMed:23589306, ECO:0000305|PubMed:20688984};
DE AltName: Full=Cycle-inhibiting factor {ECO:0000303|PubMed:14651638};
GN Name=cif {ECO:0000303|PubMed:14651638};
OS Escherichia coli.
OG Plasmid pFX13.
OC Bacteria; Proteobacteria; Gammaproteobacteria; Enterobacterales;
OC Enterobacteriaceae; Escherichia.
OX NCBI_TaxID=562;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, AND SUBCELLULAR LOCATION.
RC STRAIN=C/15333, CF11201, E22, EF26, and EF33; PLASMID=pFX13;
RX PubMed=14651638; DOI=10.1046/j.1365-2958.2003.03821.x;
RA Marches O., Ledger T.N., Boury M., Ohara M., Tu X., Goffaux F., Mainil J.,
RA Rosenshine I., Sugai M., De Rycke J., Oswald E.;
RT "Enteropathogenic and enterohaemorrhagic Escherichia coli deliver a novel
RT effector called Cif, which blocks cell cycle G2/M transition.";
RL Mol. Microbiol. 50:1553-1567(2003).
RN [2]
RP SUBCELLULAR LOCATION, TRANSLOCATION DOMAIN, AND DOMAIN.
RC STRAIN=O103:H2 / B10 / EPEC;
RX PubMed=15292151; DOI=10.1128/jb.186.16.5486-5495.2004;
RA Charpentier X., Oswald E.;
RT "Identification of the secretion and translocation domain of the
RT enteropathogenic and enterohemorrhagic Escherichia coli effector Cif, using
RT TEM-1 beta-lactamase as a new fluorescence-based reporter.";
RL J. Bacteriol. 186:5486-5495(2004).
RN [3]
RP FUNCTION.
RC STRAIN=O111:H- / B171 / EPEC;
RX PubMed=16848790; DOI=10.1111/j.1462-5822.2006.00757.x;
RA Taieb F., Nougayrede J.P., Watrin C., Samba-Louaka A., Oswald E.;
RT "Escherichia coli cyclomodulin Cif induces G2 arrest of the host cell cycle
RT without activation of the DNA-damage checkpoint-signalling pathway.";
RL Cell. Microbiol. 8:1910-1921(2006).
RN [4]
RP FUNCTION.
RC STRAIN=O111:H- / B171 / EPEC;
RX PubMed=18705694; DOI=10.1111/j.1462-5822.2008.01224.x;
RA Samba-Louaka A., Nougayrede J.P., Watrin C., Jubelin G., Oswald E.,
RA Taieb F.;
RT "Bacterial cyclomodulin Cif blocks the host cell cycle by stabilizing the
RT cyclin-dependent kinase inhibitors p21 and p27.";
RL Cell. Microbiol. 10:2496-2508(2008).
RN [5]
RP FUNCTION.
RX PubMed=17873042; DOI=10.1128/jb.00844-07;
RA Loukiadis E., Nobe R., Herold S., Tramuta C., Ogura Y., Ooka T.,
RA Morabito S., Kerouredan M., Brugere H., Schmidt H., Hayashi T., Oswald E.;
RT "Distribution, functional expression, and genetic organization of Cif, a
RT phage-encoded type III-secreted effector from enteropathogenic and
RT enterohemorrhagic Escherichia coli.";
RL J. Bacteriol. 190:275-285(2008).
RN [6]
RP FUNCTION.
RC STRAIN=O103:H2 / B10 / EPEC;
RX PubMed=19786559; DOI=10.1128/iai.00860-09;
RA Samba-Louaka A., Nougayrede J.P., Watrin C., Oswald E., Taieb F.;
RT "The enteropathogenic Escherichia coli effector Cif induces delayed
RT apoptosis in epithelial cells.";
RL Infect. Immun. 77:5471-5477(2009).
RN [7]
RP FUNCTION, ACTIVE SITE, SUBCELLULAR LOCATION, AND MUTAGENESIS OF CYS-109.
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 [8]
RP FUNCTION, ACTIVE SITES, AND MUTAGENESIS OF CYS-109; HIS-165; GLN-185 AND
RP ASP-187.
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]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RC STRAIN=O103:H2 / B10 / EPEC;
RX PubMed=20941356; DOI=10.1371/journal.ppat.1001128;
RA Jubelin G., Taieb F., Duda D.M., Hsu Y., Samba-Louaka A., Nobe R.,
RA Penary M., Watrin C., Nougayrede J.P., Schulman B.A., Stebbins C.E.,
RA Oswald E.;
RT "Pathogenic bacteria target NEDD8-conjugated cullins to hijack host-cell
RT signaling pathways.";
RL PLoS Pathog. 6:e1001128-e1001128(2010).
RN [10]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP 58-ASP-ASP-59; VAL-111; ASN-114; GLU-139; LYS-152 AND ASN-159.
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 [11]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=23589306; DOI=10.1074/jbc.m112.448258;
RA Toro T.B., Toth J.I., Petroski M.D.;
RT "The cyclomodulin cycle inhibiting factor (CIF) alters cullin neddylation
RT dynamics.";
RL J. Biol. Chem. 288:14716-14726(2013).
RN [12] {ECO:0007744|PDB:3EFY}
RP X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) OF 100-282, ACTIVE SITES, AND
RP MUTAGENESIS OF CYS-109 AND HIS-165.
RX PubMed=18845161; DOI=10.1016/j.jmb.2008.09.051;
RA Hsu Y., Jubelin G., Taieb F., Nougayrede J.P., Oswald E., Stebbins C.E.;
RT "Structure of the cyclomodulin Cif from pathogenic Escherichia coli.";
RL J. Mol. Biol. 384:465-477(2008).
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:14651638, PubMed:16848790,
CC PubMed:18705694, PubMed:17873042, PubMed:19786559, PubMed:19308257,
CC PubMed:19225106, PubMed:20941356, PubMed:20688984). Acts by mediating
CC the side chain deamidation of 'Gln-40' of host NEDD8, converting it to
CC glutamate, thereby abolishing the activity of cullin-RING-based E3
CC ubiquitin-protein ligase complexes (CRL complexes) (PubMed:20941356,
CC PubMed:20688984, PubMed:23589306). Inactivation of CRL complexes
CC prevents ubiquitination and subsequent degradation of the cyclin-
CC dependent kinase inhibitors CDKN1A/p21 and CDKN1B/p27, leading to G1
CC and G2 cell cycle arrests in host cells (PubMed:18705694,
CC PubMed:19308257, PubMed:20941356). Also able to catalyze deamidation of
CC 'Gln-40' of host ubiquitin in vitro; however, NEDD8 constitutes the
CC preferred substrate in vivo (By similarity).
CC {ECO:0000250|UniProtKB:Q63KH5, ECO:0000269|PubMed:14651638,
CC ECO:0000269|PubMed:16848790, ECO:0000269|PubMed:17873042,
CC ECO:0000269|PubMed:18705694, ECO:0000269|PubMed:19225106,
CC ECO:0000269|PubMed:19308257, ECO:0000269|PubMed:19786559,
CC ECO:0000269|PubMed:20688984, ECO:0000269|PubMed:20941356,
CC ECO:0000269|PubMed:23589306}.
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:23589306, ECO:0000305|PubMed:20688984};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16442;
CC Evidence={ECO:0000269|PubMed:23589306, ECO:0000305|PubMed:20688984};
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:15292151,
CC ECO:0000269|PubMed:19308257, ECO:0000269|PubMed:20688984,
CC ECO:0000305|PubMed:14651638}. Host nucleus
CC {ECO:0000269|PubMed:20941356}. Note=Secreted via the type III secretion
CC system (TTSS). {ECO:0000269|PubMed:14651638,
CC ECO:0000269|PubMed:15292151, ECO:0000269|PubMed:19308257,
CC ECO:0000269|PubMed:20688984}.
CC -!- DOMAIN: The translocation domain (TD) is necessary and sufficient to
CC mediate translocation into the host cells.
CC {ECO:0000269|PubMed:15292151}.
CC -!- SIMILARITY: Belongs to the Cif family. {ECO:0000305}.
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DR EMBL; AY128535; AAN07901.1; -; Genomic_DNA.
DR EMBL; AY128537; AAN07903.1; -; Genomic_DNA.
DR EMBL; AY128542; AAN07916.1; -; Genomic_DNA.
DR EMBL; AY128544; AAN07918.1; -; Genomic_DNA.
DR EMBL; AF497476; AAQ07241.1; -; Genomic_DNA.
DR RefSeq; WP_000652080.1; NZ_WVUO01000055.1.
DR PDB; 3EFY; X-ray; 1.70 A; A/B=100-282.
DR PDBsum; 3EFY; -.
DR SMR; P0DUW5; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0042025; C:host cell nucleus; IDA:UniProtKB.
DR GO; GO:0050568; F:protein-glutamine glutaminase activity; IDA:UniProtKB.
DR GO; GO:0090729; F:toxin activity; 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; Plasmid; Secreted; Toxin; Virulence.
FT CHAIN 1..282
FT /note="Protein-glutamine deamidase Cif"
FT /id="PRO_0000453902"
FT REGION 1..16
FT /note="Translocation domain (TD)"
FT /evidence="ECO:0000269|PubMed:15292151"
FT ACT_SITE 109
FT /evidence="ECO:0000305|PubMed:18845161,
FT ECO:0000305|PubMed:19225106, ECO:0000305|PubMed:19308257"
FT ACT_SITE 165
FT /evidence="ECO:0000305|PubMed:18845161,
FT ECO:0000305|PubMed:19225106"
FT ACT_SITE 185
FT /evidence="ECO:0000305|PubMed:19225106"
FT MUTAGEN 58..59
FT /note="DD->AA: Impaired ability to mediate deamidation of
FT host NEDD8 and inhibit the host cell cycle."
FT /evidence="ECO:0000269|PubMed:20688984"
FT MUTAGEN 109
FT /note="C->A,S: Abolished ability to inhibit the host cell
FT cycle. Abolished accumulation of the cyclin-dependent
FT kinase inhibitors CDKN1A/p21 and CDKN1B/p27."
FT /evidence="ECO:0000269|PubMed:18845161,
FT ECO:0000269|PubMed:19225106, ECO:0000269|PubMed:19308257"
FT MUTAGEN 111
FT /note="V->A: No effect; does not affect ability to mediate
FT deamidation of host NEDD8."
FT /evidence="ECO:0000269|PubMed:20688984"
FT MUTAGEN 114
FT /note="N->A: Impaired ability to mediate deamidation of
FT host NEDD8 and inhibit the host cell cycle; when associated
FT with A-159."
FT /evidence="ECO:0000269|PubMed:20688984"
FT MUTAGEN 139
FT /note="E->A: No effect; does not affect ability to mediate
FT deamidation of host NEDD8."
FT /evidence="ECO:0000269|PubMed:20688984"
FT MUTAGEN 152
FT /note="K->A: No effect; does not affect ability to mediate
FT deamidation of host NEDD8."
FT /evidence="ECO:0000269|PubMed:20688984"
FT MUTAGEN 159
FT /note="N->A: Impaired ability to mediate deamidation of
FT host NEDD8 and inhibit the host cell cycle; when associated
FT with A-114."
FT /evidence="ECO:0000269|PubMed:20688984"
FT MUTAGEN 165
FT /note="H->N: Abolished ability to inhibit the host cell
FT cycle."
FT /evidence="ECO:0000269|PubMed:18845161,
FT ECO:0000269|PubMed:19225106"
FT MUTAGEN 185
FT /note="Q->A: Abolished ability to inhibit the host cell
FT cycle."
FT /evidence="ECO:0000269|PubMed:19225106"
FT MUTAGEN 187
FT /note="D->N: Does not affect ability to inhibit the host
FT cell cycle."
FT /evidence="ECO:0000269|PubMed:19225106"
SQ SEQUENCE 282 AA; 31753 MW; 632C5FAF1B6CC939 CRC64;
MKDITLPPPT SASCLTGAIS VNTEAVLSPM QHTSALHVRD FASLCSQNLK ANVLLNSDDH
EVPIHQKNPA AIMQNIDSNI KQMATDWGMS IEEVEVIIGR EKGIVEPSCG VTANAIMKLF
LDKDGFSYCF ENEQTLSLEQ LQERLSCMPE CKSFVLRVND GALGHAYIVD IPKGENSCRP
AFLYQSDLGE GVTRKLRFED WMTHKALTPI LLDDICNYFS CMSQNKTDLE QIATLFDIDG
NVKMLRKENI QYQKHDNFSF QLFEYDTDNI EKNIEIIKSL CS
