GENTAUR Molecular Products.

 PATOX_PHOAA             Reviewed;        2957 AA.
 C7BKP9;
 11-NOV-2015, integrated into UniProtKB/Swiss-Prot.
 22-SEP-2009, sequence version 1.
 23-MAY-2018, entry version 39.
 RecName: Full=Toxin PAU_02230 {ECO:0000305};
 AltName: Full=Photorhabdus asymbiotica toxin {ECO:0000303|PubMed:24141704};
          Short=PaTox {ECO:0000303|PubMed:24141704};
 Includes:
   RecName: Full=Protein N-acetylglucosaminyltransferase {ECO:0000305|PubMed:24141704};
            Short=Protein O-GlcNAc transferase {ECO:0000305|PubMed:24141704};
            EC=2.4.1.- {ECO:0000269|PubMed:24141704};
   AltName: Full=PaToxG {ECO:0000303|PubMed:24141704};
   AltName: Full=Tyrosine glycosyltransferase {ECO:0000303|PubMed:24141704};
 Includes:
   RecName: Full=Protein-glutamine amidohydrolase {ECO:0000305|PubMed:24141704};
            EC=3.5.1.44 {ECO:0000269|PubMed:24141704};
   AltName: Full=Glutamine deamidase {ECO:0000303|PubMed:24141704};
   AltName: Full=PaToxD {ECO:0000303|PubMed:24141704};
   AltName: Full=Protein-glutamine glutaminase {ECO:0000305};
 OrderedLocusNames=PAU_02230 {ECO:0000312|EMBL:CAQ84322.1};
 Photorhabdus asymbiotica subsp. asymbiotica (strain ATCC 43949 /
 3105-77) (Xenorhabdus luminescens (strain 2)).
 Bacteria; Proteobacteria; Gammaproteobacteria; Enterobacterales;
 Morganellaceae; Photorhabdus.
 NCBI_TaxID=553480 {ECO:0000312|Proteomes:UP000002747};
 [1]
 NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
 STRAIN=ATCC 43949 / 3105-77;
 PubMed=19583835; DOI=10.1186/1471-2164-10-302;
 Wilkinson P., Waterfield N.R., Crossman L., Corton C.,
 Sanchez-Contreras M., Vlisidou I., Barron A., Bignell A., Clark L.,
 Ormond D., Mayho M., Bason N., Smith F., Simmonds M., Churcher C.,
 Harris D., Thompson N.R., Quail M., Parkhill J.,
 ffrench-Constant R.H.;
 "Comparative genomics of the emerging human pathogen Photorhabdus
 asymbiotica with the insect pathogen Photorhabdus luminescens.";
 BMC Genomics 10:302-302(2009).
 [2]
 SUBCELLULAR LOCATION, AND MUTAGENESIS OF 2134-ARG-LYS-2135 AND
 2139-ARG-LYS-2140.
 STRAIN=ATCC 43950;
 PubMed=25782990; DOI=10.1096/fj.14-269381;
 Jank T., Trillhaase C., Brozda N., Steinemann M., Schwan C., Suess R.,
 Aktories K.;
 "Intracellular plasma membrane guidance of Photorhabdus asymbiotica
 toxin is crucial for cell toxicity.";
 FASEB J. 29:2789-2802(2015).
 [3]
 X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 2114-2449 IN COMPLEX WITH
 CALCIUM AND UDP-GLCNAC, FUNCTION, CATALYTIC ACTIVITY, COFACTOR,
 SUBSTRATE SPECIFICITY, DOMAIN, AND MUTAGENESIS OF TRP-2170; ASP-2260;
 ARG-2263; ASP-2276; ASP-2278; ASP-2279; 2276-ASP--ASP-2279; ASN-2312
 AND CYS-2509.
 STRAIN=ATCC 43950;
 PubMed=24141704; DOI=10.1038/nsmb.2688;
 Jank T., Bogdanovic X., Wirth C., Haaf E., Spoerner M., Boehmer K.E.,
 Steinemann M., Orth J.H., Kalbitzer H.R., Warscheid B., Hunte C.,
 Aktories K.;
 "A bacterial toxin catalyzing tyrosine glycosylation of Rho and
 deamidation of Gq and Gi proteins.";
 Nat. Struct. Mol. Biol. 20:1273-1280(2013).
 -!- FUNCTION: Toxin that acts on host cells by modifying Rho proteins
     by tyrosine GlcNAcylation and heterotrimeric G alpha proteins by
     deamidation. Catalyzes the mono-O-GlcNAcylation of small GTPases
     of the Rho family (RhoA, RhoB, RhoC, Rac1, Rac2, Rac3, Cdc42) in
     eukaryotic host cells at the conserved tyrosine residue located in
     the switch I region (Tyr-32/34), using UDP-N-acetylglucosamine
     (UDP-GlcNAc) as the sugar donor; other GTPases of the Rho, Ras or
     Rab families are not substrates. Tyrosine glycosylation inhibits
     Rho activation and prevents interaction with downstream effectors,
     resulting in actin disassembly, inhibition of phagocytosis, cell
     rounding, and toxicity toward insects and mammalian cells. Also
     catalyzes the deamidation of the catalytic glutamine in
     heterotrimeric G alpha proteins (Gi, Gq/11), which blocks GTP
     hydrolysis and arrests the G proteins in a permanent active state
     leading to activation of Rho GTPases. Thus, PaTox hijacks host
     GTPase signaling in a bidirectional manner by deamidation-induced
     activation and glycosylation-induced inactivation of GTPases.
     {ECO:0000269|PubMed:24141704}.
 -!- CATALYTIC ACTIVITY: UDP-N-acetyl-alpha-D-glucosamine + [protein]-
     L-tyrosine = UDP + [protein]-O-(N-acetyl-alpha-D-glucosaminyl)-L-
     tyrosine. {ECO:0000269|PubMed:24141704}.
 -!- CATALYTIC ACTIVITY: Protein L-glutamine + H(2)O = protein L-
     glutamate + NH(3). {ECO:0000269|PubMed:24141704}.
 -!- COFACTOR:
     Name=a divalent metal cation; Xref=ChEBI:CHEBI:60240;
       Evidence={ECO:0000269|PubMed:24141704};
     Note=A Ca(2+) ion is seen in the structure.
     {ECO:0000269|PubMed:24141704};
 -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305}. Host cell membrane
     {ECO:0000269|PubMed:25782990}; Peripheral membrane protein
     {ECO:0000269|PubMed:25782990}; Cytoplasmic side
     {ECO:0000269|PubMed:25782990}. Note=Associates with the negatively
     charged inner leaflet of the plasma membrane via interaction with
     phosphatidylserine and phosphatidylinositolphosphates. Plasma
     membrane localization of PaTox is essential for cytotoxicity. The
     glycosyltransferase domain alone is sufficient to localize at the
     plasma membrane. {ECO:0000269|PubMed:25782990}.
 -!- DOMAIN: In the C-terminal region, contains two catalytic domains:
     a glycosyltransferase (PaToxG) and a deamidase domain (PaToxD).
     The N-terminal region contains a receptor-translocation domain
     necessary for toxin entry into the cytoplasm of host cell.
     {ECO:0000269|PubMed:24141704}.
 -!- MISCELLANEOUS: The active GTP-bound conformation of Rho is the
     preferred substrate for PaTox-induced glycosylation.
     {ECO:0000269|PubMed:24141704}.
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 EMBL; FM162591; CAQ84322.1; -; Genomic_DNA.
 PDB; 4MIX; X-ray; 1.80 A; A/B=2114-2449.
 PDBsum; 4MIX; -.
 SMR; C7BKP9; -.
 STRING; 553480.PAU_02230; -.
 PRIDE; C7BKP9; -.
 EnsemblBacteria; CAQ84322; CAQ84322; PAU_02230.
 KEGG; pay:PAU_02230; -.
 eggNOG; ENOG4106EE1; Bacteria.
 eggNOG; ENOG410Y12W; LUCA.
 OrthoDB; POG091H070A; -.
 Proteomes; UP000002747; Chromosome.
 GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
 GO; GO:0020002; C:host cell plasma membrane; IEA:UniProtKB-SubCell.
 GO; GO:0016020; C:membrane; IEA:UniProtKB-KW.
 GO; GO:0005509; F:calcium ion binding; IDA:UniProtKB.
 GO; GO:0016262; F:protein N-acetylglucosaminyltransferase activity; IDA:UniProtKB.
 GO; GO:0050568; F:protein-glutamine glutaminase activity; IDA:UniProtKB.
 GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
 GO; GO:0036210; P:protein modification process in other organism; IDA:UniProtKB.
 GO; GO:0043087; P:regulation of GTPase activity; IDA:UniProtKB.
 InterPro; IPR007577; GlycoTrfase_DXD_sugar-bd_CS.
 InterPro; IPR029044; Nucleotide-diphossugar_trans.
 InterPro; IPR028907; Tox-PLDMTX_dom.
 Pfam; PF04488; Gly_transf_sug; 1.
 Pfam; PF15645; Tox-PLDMTX; 1.
 SUPFAM; SSF53448; SSF53448; 2.
 1: Evidence at protein level;
 3D-structure; Calcium; Complete proteome; Glycosyltransferase;
 Host cell membrane; Host membrane; Hydrolase; Membrane; Metal-binding;
 Multifunctional enzyme; Reference proteome; Secreted; Toxin;
 Transferase; Virulence.
 CHAIN         1   2957       Toxin PAU_02230.
                              /FTId=PRO_0000434568.
 REGION     2115   2449       Tyrosine glycosyltransferase PaToxG.
                              {ECO:0000305|PubMed:24141704}.
 REGION     2115   2144       Membrane localization domain that
                              interacts with the inner leaflet of the
                              plasma membrane.
                              {ECO:0000269|PubMed:25782990}.
 REGION     2169   2171       UDP-GlcNAc binding.
                              {ECO:0000269|PubMed:24141704}.
 REGION     2259   2260       UDP-GlcNAc binding.
                              {ECO:0000269|PubMed:24141704}.
 REGION     2450   2672       SseI-like deamidase PaToxD.
                              {ECO:0000305|PubMed:24141704}.
 MOTIF      2276   2279       DxDD motif.
                              {ECO:0000305|PubMed:24141704}.
 ACT_SITE   2509   2509       For deamidase activity.
                              {ECO:0000305|PubMed:24141704}.
 ACT_SITE   2547   2547       For deamidase activity.
                              {ECO:0000305|PubMed:24141704}.
 ACT_SITE   2562   2562       For deamidase activity.
                              {ECO:0000305|PubMed:24141704}.
 METAL      2276   2276       Divalent metal cation.
                              {ECO:0000244|PDB:4MIX,
                              ECO:0000305|PubMed:24141704}.
 METAL      2278   2278       Divalent metal cation.
                              {ECO:0000244|PDB:4MIX,
                              ECO:0000305|PubMed:24141704}.
 BINDING    2312   2312       UDP-GlcNAc.
                              {ECO:0000269|PubMed:24141704}.
 MUTAGEN    2134   2135       RK->EE: Abrogates plasma membrane
                              localization, resulting in a cytosolic
                              distribution of this mutant protein. Loss
                              of toxic activity on host cells during
                              the first hours of incubation. No effect
                              on glycosyltransferase activity and
                              interaction with RhoA.
                              {ECO:0000269|PubMed:25782990}.
 MUTAGEN    2139   2140       RK->EE: Abrogates plasma membrane
                              localization, resulting in a cytosolic
                              distribution of this mutant protein. Loss
                              of toxic activity on host cells during
                              the first hours of incubation. No effect
                              on glycosyltransferase activity and
                              interaction with RhoA.
                              {ECO:0000269|PubMed:25782990}.
 MUTAGEN    2170   2170       W->A: 7-fold reduction in
                              glycosyltransferase activity.
                              {ECO:0000269|PubMed:24141704}.
 MUTAGEN    2260   2260       D->A: 10000-fold reduction in
                              glycosyltransferase activity. Reduced
                              cell toxicity.
                              {ECO:0000269|PubMed:24141704}.
 MUTAGEN    2263   2263       R->A: 2000-fold reduction in
                              glycosyltransferase activity. Reduced
                              cell toxicity.
                              {ECO:0000269|PubMed:24141704}.
 MUTAGEN    2276   2278       DID->NIN: Loss of glycosyltransferase
                              activity. Reduced toxicity in insect
                              larvae. Loss of the ability to block
                              phagocytosis in mammalian macrophages.
                              Loss of effect on actin skeleton.
                              {ECO:0000269|PubMed:24141704}.
 MUTAGEN    2276   2276       D->N: 16700-fold reduction in
                              glycosyltransferase activity.
                              {ECO:0000269|PubMed:24141704}.
 MUTAGEN    2278   2278       D->N: 333-fold reduction in
                              glycosyltransferase activity.
                              {ECO:0000269|PubMed:24141704}.
 MUTAGEN    2279   2279       D->N: 700-fold reduction in
                              glycosyltransferase activity.
                              {ECO:0000269|PubMed:24141704}.
 MUTAGEN    2312   2312       N->A: 1.3-fold reduction in
                              glycosyltransferase activity.
                              {ECO:0000269|PubMed:24141704}.
 MUTAGEN    2509   2509       C->S: Loss of deamidase activity.
                              {ECO:0000269|PubMed:24141704}.
 HELIX      2132   2153       {ECO:0000244|PDB:4MIX}.
 STRAND     2164   2169       {ECO:0000244|PDB:4MIX}.
 STRAND     2172   2174       {ECO:0000244|PDB:4MIX}.
 HELIX      2178   2189       {ECO:0000244|PDB:4MIX}.
 STRAND     2194   2200       {ECO:0000244|PDB:4MIX}.
 HELIX      2208   2218       {ECO:0000244|PDB:4MIX}.
 STRAND     2221   2227       {ECO:0000244|PDB:4MIX}.
 HELIX      2228   2230       {ECO:0000244|PDB:4MIX}.
 HELIX      2234   2239       {ECO:0000244|PDB:4MIX}.
 HELIX      2241   2251       {ECO:0000244|PDB:4MIX}.
 HELIX      2255   2270       {ECO:0000244|PDB:4MIX}.
 STRAND     2272   2274       {ECO:0000244|PDB:4MIX}.
 HELIX      2291   2293       {ECO:0000244|PDB:4MIX}.
 STRAND     2312   2317       {ECO:0000244|PDB:4MIX}.
 HELIX      2322   2337       {ECO:0000244|PDB:4MIX}.
 HELIX      2343   2346       {ECO:0000244|PDB:4MIX}.
 HELIX      2348   2358       {ECO:0000244|PDB:4MIX}.
 HELIX      2360   2362       {ECO:0000244|PDB:4MIX}.
 HELIX      2364   2382       {ECO:0000244|PDB:4MIX}.
 HELIX      2399   2412       {ECO:0000244|PDB:4MIX}.
 TURN       2413   2417       {ECO:0000244|PDB:4MIX}.
 STRAND     2418   2420       {ECO:0000244|PDB:4MIX}.
 SEQUENCE   2957 AA;  334884 MW;  AE0C52A8C11E4C6B CRC64;
 MKGIEGVIML SHDILPEKLL VSEKKHENVG SYFSDDIGEQ SEQTEVSHFN LSLDDAFDIY
 ADISIENQQE LKNKDNNTNI WSSLGRGDDD HNLKKIINDA FKEKLPQLME YRRKGYNVIG
 LDKEGIKKLE GMLKAVPPEI QQPTMKNLYS AAQELLNTLK QHPLLPENQD MIQQSNLVIR
 NLSDALEAIN AVSKVNQVEW WEEVHKTNKA QSDRLIAATL EELFFKVKDK RLPGSNDDYC
 QQEREETERK IKDLLLYDGY QLTAEHFKFG RLRKSLLAES RVTRLKLAEY LEKKSVGILT
 AARDAKMYAM KILLAQTRNN GFNAKDLINA GQVNDRLLSF QQYARHIRAV DGEIDGIILS
 NPLVVACIKE TNDEPAHIKI ARAILPVSEE LGTVSKVLRE TKEKVQPSKP KEELNHPHQD
 WWNRGDELWK YIKKTSWNIK ETSVHVTQMV GYEASKTASR AKHKLKESSY SESINGAVKG
 TALLLLDEIQ QAENRIRQIP QFAWDVQEAV EQHSSVIQRT AYPDELPELS ELLNEQLKHE
 EARWQAVKKQ SRDKLQELIA PITRLAQEKW AQDLYFQLGE ELRKERQDRW KDIQQFDEIM
 AEAVGQFAEM ARELDSEAVR LAEHGHSGGK ELQEKVAKWL RDLSKLKGKV KAGVAKITGT
 SLDNFSRSGM LARGMSEWAE DLKQSYLQET LQEGSAVAAE LFERTLMEVV EENRTHFAKE
 SDPEAERFLK RLALALKHAA ENTTVYPPTP EEILAGSRSL PEDIRHWAEK KVVSGAISAA
 FRGGFKLVTG TFSLPVRVVI RGAKTGGTLY RGVRAINRSV RLGQGPATQV KSKFINQELS
 KTAFRLTLSL SPLVAWGMAA SITAGRLYNE KDYPEKIIKN IVIDLPEELL WIGGYAGINA
 AIRAHAEKAI QQAIQHALDE QADKLALRIN KEIAGKSADV NVEIIPQETS VSPAETAQST
 PEPLSDFAST SQLTMPELID IQDNNSAQQP KVRRKRDVSV ESEISIDNLN IINANTREDK
 VNSEIKSELR SELKRFENSD ANSPMSDVER AIFIDLFLYK NKYEVSESQQ DYKNTWLKFR
 RELESQENKE IKEYLRFRSI IEAYEIYDKK RLDDDTIPEA GTIIKEVIDF FQKLKKENPI
 TFMKLAEAMV KFQYYYEEED ENEDRYFKMA EIYYFLNKTE NEKKSKTFHL DIIDKYPNEN
 NRLLDEFFLN KNNNNPDLDE IIYKLQSMQE KYRESYEMLS KVENIHQVLS DDSKNEENIF
 LDNRIIAAQV FDGSINISLQ DKKKWLNRYD QIRNEEGSDG WKLMHIESIL INLRRINTAI
 NLTAMKSESA LLLIDKLLNF QKKARENILH ISETPHEDFT SYSQFKTRKE LGNDDSKYYA
 QFDNYKDNHD AEKEAKEILS QVVARASLSF SELFDKVESI KLFSFVYKNR DGGAPLAAPG
 RTVVIKFPGK DTGGLVISNL FLRNHVKRIS TKEMEDLKPL TEGMYTRATQ HRSLGSYYHI
 GSQSEHTNAL EILSGMNKEE LKTHLKKQGI WFGEPALFSN EYPKQENTGH LENTTLKNAI
 IGVSTIQNNA AANYLRSTMY ESTGWEKLGD RFIPFYEIGR RKHYDREYEI NSEQLTLDII
 TSIAIAYPAA RGIVATIRSS AIPSILKSGL RGSALFKSLS LELGKMGFNA SKVFGGAVYE
 LIEPYPINSH LNRHNVFNKV KDTAWEFHTD VGLKGGGLKD FIDRFTKEPK EITISGYKFK
 RIKYNQENFD TMQRMALDYA YNPDSKGKIA QAQQAYKTGK EDYNAPQYDN FNGLSLDKKI
 ERYISPDTDA TTKGVLAGKM NESIKDINAF QTAKDAQSWK KSANKANKVV LTPQNLYLKG
 KPSECLPESV LMGWALQSSQ DAKLSKMLMG IYSSNDITSN PLYKSLKELH ANGNASKFNA
 SATSISNINV SNLATSETKL FPTEISSVRV DAPKHTMLIS KIKNRENKIK YVFYDPNYGM
 AYFDKHSDMA AFFQKKMQQY DFPDDSVSFH PLDYSNVSDI KISGRNLNEI IDGEIPLLYK
 QEGVQLEGIT PRDGIYRVPP KNTLGVQETK HYIIVNNDIY QVEWDQTNNT WRVFDPSNTN
 RSRPTVPVKQ DTNGEWFKHS ETGLKGGGPI DDIRKYIARK SAIKIFNQSI NYSATKWPPE
 PIDKNIHMIW IGTKNISEKN IKLSIDTAKK NPDYNTSIIY DSGISGHEGA KKFMLEKFQD
 SNVNIIDFRK KSYFSQLKQE PSFAYYEQVI AENKYAQASD ILRLLVLKYE GGIYKDIDDI
 QVKGFGSLTF PKGIGVMREY APEAGKATAF PNTPIAVTKN NPIINKTLDL AVSNYQRGEK
 NVLKLAGPDV FTQALYQEIP GLDSKVLNAQ LYQLELAKRQ ALGVPLEKPK NFADEQLTSA
 EKEKINRPYQ SIRGLSGYVE NGADHSWAVD TNIPSTSTQT STIVTPLAPK TEMLPPVPSS
 STKSSTSAPV LQEKISYNLA TDIDATDYLN QLKQKTNINN KISSPAGQCE SLMKPVSDFM
 RENGFTDIRY RGMFIWNNAT EQIPMNHFVV VGKKVGKDYV FDVSAHQFEN KGMPDLNGPL
 ILAAEDWAKK YRGATTRKLI YYSDFKNAST ATNTYNALPR ELVLESMEGK TFITSPNWYQ
 TFKRTHNIHP EVTVSDPATF SLNYSVNPTA ENLSPPPPPP IPSHGQVPKT VTPPPPPMRS
 PLSLSQPLER LPANKTKPIG FNPGENKASF SKLEEAGKHY YKDDKSRQAA PVNTMSDFDN
 RYLSHTTEAP APSNVAHLAP GNIYNTKVTA KGAEKPAYDI YISKDGESLI TSSSYKVDDI
 TTDSKFGKPL PYSEIMFNSL KKSGVDPKNL KRSVQASIEN KVTQDVISAI GTRIQRGQVI
 RVSPTENPDA FYTLLGTDNC KATLHMLNQH AEEFGHKVVT SIEFKGTGYL VMNIGTSTQT
 STIVTPPPMP GTSQLVQ

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