ADPRS_HUMAN
ID ADPRS_HUMAN Reviewed; 363 AA.
AC Q9NX46; Q53G94; Q6IAB8; Q9BY47;
DT 06-FEB-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2000, sequence version 1.
DT 03-AUG-2022, entry version 172.
DE RecName: Full=ADP-ribosylhydrolase ARH3 {ECO:0000305};
DE AltName: Full=ADP-ribose glycohydrolase ARH3 {ECO:0000305};
DE AltName: Full=ADP-ribosylhydrolase 3 {ECO:0000303|PubMed:16278211};
DE AltName: Full=O-acetyl-ADP-ribose deacetylase ARH3 {ECO:0000305};
DE EC=3.5.1.- {ECO:0000269|PubMed:17075046, ECO:0000269|PubMed:21498885};
DE AltName: Full=Poly(ADP-ribose) glycohydrolase ARH3 {ECO:0000305};
DE EC=3.2.1.143 {ECO:0000269|PubMed:16278211, ECO:0000269|PubMed:17075046, ECO:0000269|PubMed:22433848};
DE AltName: Full=[Protein ADP-ribosylarginine] hydrolase-like protein 2 {ECO:0000305};
DE AltName: Full=[Protein ADP-ribosylserine] hydrolase {ECO:0000305};
DE EC=3.2.2.- {ECO:0000269|PubMed:28650317, ECO:0000269|PubMed:29234005};
GN Name=ADPRS {ECO:0000312|HGNC:HGNC:21304};
GN Synonyms=ADPRHL2, ARH3 {ECO:0000303|PubMed:16278211};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX PubMed=12070318; DOI=10.1110/ps.0200602;
RA Glowacki G., Braren R., Firner K., Nissen M., Kuehl M., Reche P.,
RA Bazan J.F., Cetkovic-Cvrlje M., Leiter E., Haag F., Koch-Nolte F.;
RT "The family of toxin-related ecto-ADP-ribosyltransferases in humans and the
RT mouse.";
RL Protein Sci. 11:1657-1670(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver cancer;
RA Li Y., Wu T., Xu S., Ren S., Chen Z., Han Z.;
RT "A novel gene expressed in human liver cancer tissue.";
RL Submitted (DEC-1999) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT LYS-209.
RC TISSUE=Thyroid;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP FUNCTION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, COFACTOR, AND
RP MUTAGENESIS OF 77-ASP--ASP-78; 238-GLU--GLU-239 AND 261-GLU--GLU-262.
RX PubMed=16278211; DOI=10.1074/jbc.m510290200;
RA Oka S., Kato J., Moss J.;
RT "Identification and characterization of a mammalian 39-kDa poly(ADP-ribose)
RT glycohydrolase.";
RL J. Biol. Chem. 281:705-713(2006).
RN [9]
RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, AND MUTAGENESIS OF 77-ASP-ASP-78;
RP 261-GLU-GLU-262 AND 238-GLU-GLN-239.
RX PubMed=17075046; DOI=10.1073/pnas.0607911103;
RA Ono T., Kasamatsu A., Oka S., Moss J.;
RT "The 39-kDa poly(ADP-ribose) glycohydrolase ARH3 hydrolyzes O-acetyl-ADP-
RT ribose, a product of the Sir2 family of acetyl-histone deacetylases.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:16687-16691(2006).
RN [10]
RP SUBCELLULAR LOCATION.
RX PubMed=17991898; DOI=10.1128/mcb.01766-07;
RA Niere M., Kernstock S., Koch-Nolte F., Ziegler M.;
RT "Functional localization of two poly(ADP-ribose)-degrading enzymes to the
RT mitochondrial matrix.";
RL Mol. Cell. Biol. 28:814-824(2008).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [12]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=21498885; DOI=10.1074/jbc.m111.237636;
RA Kasamatsu A., Nakao M., Smith B.C., Comstock L.R., Ono T., Kato J.,
RA Denu J.M., Moss J.;
RT "Hydrolysis of O-acetyl-ADP-ribose isomers by ADP-ribosylhydrolase 3.";
RL J. Biol. Chem. 286:21110-21117(2011).
RN [13]
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=22433848; DOI=10.1074/jbc.m112.349183;
RA Niere M., Mashimo M., Agledal L., Dolle C., Kasamatsu A., Kato J., Moss J.,
RA Ziegler M.;
RT "ADP-ribosylhydrolase 3 (ARH3), not poly(ADP-ribose) glycohydrolase (PARG)
RT isoforms, is responsible for degradation of mitochondrial matrix-associated
RT poly(ADP-ribose).";
RL J. Biol. Chem. 287:16088-16102(2012).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22223895; DOI=10.1074/mcp.m111.015131;
RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T.,
RA Giglione C.;
RT "Comparative large-scale characterisation of plant vs. mammal proteins
RT reveals similar and idiosyncratic N-alpha acetylation features.";
RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-64, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [17]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF ASP-77; 77-ASP--ASP-78 AND
RP ASP-78.
RX PubMed=28650317; DOI=10.7554/elife.28533;
RA Fontana P., Bonfiglio J.J., Palazzo L., Bartlett E., Matic I., Ahel I.;
RT "Serine ADP-ribosylation reversal by the hydrolase ARH3.";
RL Elife 6:0-0(2017).
RN [18]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF GLU-41; ASP-77;
RP 77-ASP-ASP-78; GLY-115; SER-148; TYR-149; HIS-182; ASP-314 AND THR-317.
RX PubMed=29234005; DOI=10.1038/s41467-017-02253-1;
RA Abplanalp J., Leutert M., Frugier E., Nowak K., Feurer R., Kato J.,
RA Kistemaker H.V.A., Filippov D.V., Moss J., Caflisch A., Hottiger M.O.;
RT "Proteomic analyses identify ARH3 as a serine mono-ADP-ribosylhydrolase.";
RL Nat. Commun. 8:2055-2055(2017).
RN [19]
RP FUNCTION.
RX PubMed=29480802; DOI=10.7554/elife.34334;
RA Palazzo L., Leidecker O., Prokhorova E., Dauben H., Matic I., Ahel I.;
RT "Serine is the major residue for ADP-ribosylation upon DNA damage.";
RL Elife 7:0-0(2018).
RN [20]
RP CATALYTIC ACTIVITY, AND MUTAGENESIS OF ASP-77 AND ASP-78.
RX PubMed=31599159; DOI=10.1021/acschembio.9b00429;
RA Stevens L.A., Kato J., Kasamatsu A., Oda H., Lee D.Y., Moss J.;
RT "The ARH and Macrodomain Families of alpha-ADP-ribose-acceptor Hydrolases
RT Catalyze alpha-NAD+ Hydrolysis.";
RL ACS Chem. Biol. 14:2576-2584(2019).
RN [21]
RP FUNCTION, TISSUE SPECIFICITY, AND INVOLVEMENT IN CONDSIAS.
RX PubMed=30830864; DOI=10.1172/jci.insight.124519;
RA Mashimo M., Bu X., Aoyama K., Kato J., Ishiwata-Endo H., Stevens L.A.,
RA Kasamatsu A., Wolfe L.A., Toro C., Adams D., Markello T., Gahl W.A.,
RA Moss J.;
RT "PARP1 inhibition alleviates injury in ARH3-deficient mice and human
RT cells.";
RL JCI Insight 4:0-0(2019).
RN [22]
RP FUNCTION, AND MUTAGENESIS OF ASP-77 AND ASP-78.
RX PubMed=33769608; DOI=10.1002/chem.202100337;
RA Voorneveld J., Rack J.G.M., van Gijlswijk L., Meeuwenoord N.J., Liu Q.,
RA Overkleeft H.S., van der Marel G.A., Ahel I., Filippov D.V.;
RT "Molecular Tools for the Study of ADP-Ribosylation: A Unified and Versatile
RT Method to Synthesise Native Mono-ADP-Ribosylated Peptides.";
RL Chemistry 27:10621-10627(2021).
RN [23]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 19-363, SUBUNIT, AND MUTAGENESIS
RP OF GLU-41; ASP-77; SER-148; TYR-149; ASN-151; HIS-182; ASP-314 AND THR-317.
RX PubMed=17015823; DOI=10.1073/pnas.0606762103;
RA Mueller-Dieckmann C., Kernstock S., Lisurek M., von Kries J.P., Haag F.,
RA Weiss M.S., Koch-Nolte F.;
RT "The structure of human ADP-ribosylhydrolase 3 (ARH3) provides insights
RT into the reversibility of protein ADP-ribosylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:15026-15031(2006).
RN [24]
RP X-RAY CRYSTALLOGRAPHY (1.82 ANGSTROMS) OF 19-363, SUBSTRATE-BINDING SITE,
RP AND METAL-BINDING SITES.
RX PubMed=21892188; DOI=10.1038/nature10404;
RA Slade D., Dunstan M.S., Barkauskaite E., Weston R., Lafite P., Dixon N.,
RA Ahel M., Leys D., Ahel I.;
RT "The structure and catalytic mechanism of a poly(ADP-ribose)
RT glycohydrolase.";
RL Nature 477:616-620(2011).
RN [25]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=33186521; DOI=10.1016/j.cell.2020.09.055;
RA Bonfiglio J.J., Leidecker O., Dauben H., Longarini E.J., Colby T.,
RA San Segundo-Acosta P., Perez K.A., Matic I.;
RT "An HPF1/PARP1-based chemical biology strategy for exploring ADP-
RT ribosylation.";
RL Cell 183:1086-1102(2020).
RN [26]
RP PRELIMINARY X-RAY CRYSTALLOGRAPHY (1.13 ANGSTROMS) OF 18-363 IN COMPLEX
RP WITH ADP, AND SUBUNIT.
RX PubMed=16511307; DOI=10.1107/s1744309106003435;
RA Kernstock S., Koch-Nolte F., Mueller-Dieckmann J., Weiss M.S.,
RA Mueller-Dieckmann C.;
RT "Cloning, expression, purification, crystallization and preliminary X-ray
RT diffraction analysis of human ARH3, the first eukaryotic protein-ADP-
RT ribosylhydrolase.";
RL Acta Crystallogr. F 62:224-227(2006).
RN [27] {ECO:0007744|PDB:2G4K}
RP X-RAY CRYSTALLOGRAPHY (1.82 ANGSTROMS) OF 18-363 IN COMPLEX WITH MAGNESIUM,
RP AND COFACTOR.
RX PubMed=17327674; DOI=10.1107/s0907444906055624;
RA Mueller-Dieckmann C., Panjikar S., Schmidt A., Mueller S., Kuper J.,
RA Geerlof A., Wilmanns M., Singh R.K., Tucker P.A., Weiss M.S.;
RT "On the routine use of soft X-rays in macromolecular crystallography. Part
RT IV. Efficient determination of anomalous substructures in biomacromolecules
RT using longer X-ray wavelengths.";
RL Acta Crystallogr. D 63:366-380(2007).
RN [28] {ECO:0007744|PDB:5ZQY}
RP X-RAY CRYSTALLOGRAPHY (1.58 ANGSTROMS) OF 19-363 IN COMPLEX WITH MAGNESIUM
RP AND ADP-RIBOSE, FUNCTION, COFACTOR, ACTIVITY REGULATION, SUBCELLULAR
RP LOCATION, AND MUTAGENESIS OF GLU-41; ASP-77; SER-148; TYR-149; HIS-182;
RP ASP-314 AND THR-317.
RX PubMed=30045870; DOI=10.1074/jbc.ra118.004284;
RA Wang M., Yuan Z., Xie R., Ma Y., Liu X., Yu X.;
RT "Structure-function analyses reveal the mechanism of the ARH3-dependent
RT hydrolysis of ADP-ribosylation.";
RL J. Biol. Chem. 293:14470-14480(2018).
RN [29] {ECO:0007744|PDB:6D36, ECO:0007744|PDB:6D3A}
RP X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) IN COMPLEX WITH MAGNESIUM AND
RP ADP-RIBOSE, FUNCTION, SUBSTRATE SPECIFICITY, ACTIVITY REGULATION, COFACTOR,
RP AND MUTAGENESIS OF ASP-314.
RX PubMed=29907568; DOI=10.1074/jbc.ra118.003586;
RA Pourfarjam Y., Ventura J., Kurinov I., Cho A., Moss J., Kim I.K.;
RT "Structure of human ADP-ribosyl-acceptor hydrolase 3 bound to ADP-ribose
RT reveals a conformational switch that enables specific substrate
RT recognition.";
RL J. Biol. Chem. 293:12350-12359(2018).
RN [30] {ECO:0007744|PDB:7L9F, ECO:0007744|PDB:7L9H, ECO:0007744|PDB:7L9I}
RP X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) IN COMPLEX WITH MAGNESIUM AND
RP ADP-RIBOSE, FUNCTION, COFACTOR, AND MUTAGENESIS OF ASP-77; ASP-78; ASP-314
RP AND ASP-316.
RX PubMed=33894202; DOI=10.1016/j.jbc.2021.100692;
RA Pourfarjam Y., Ma Z., Kurinov I., Moss J., Kim I.K.;
RT "Structural and biochemical analysis of human ADP-ribosyl-acceptor
RT hydrolase 3 reveals the basis of metal selectivity and different roles for
RT the two magnesium ions.";
RL J. Biol. Chem. 296:100692-100692(2021).
RN [31] {ECO:0007744|PDB:7AKR, ECO:0007744|PDB:7AKS, ECO:0007744|PDB:7ARW}
RP X-RAY CRYSTALLOGRAPHY (1.31 ANGSTROMS) OF 19-363 OF VARIANT ALA-41 IN
RP COMPLEX WITH ADP-RIBOSE; HISTONE 2B AND NAD, FUNCTION, CATALYTIC ACTIVITY,
RP ACTIVITY REGULATION, AND MUTAGENESIS OF ASP-34; GLU-41; THR-76; ASP-77;
RP ASP-78; GLY-115; PHE-143; SER-148; TYR-149; GLY-150; SER-185; LEU-186;
RP ASN-269; GLY-270 AND ILE-271.
RX PubMed=34321462; DOI=10.1038/s41467-021-24723-3;
RA Rack J.G.M., Liu Q., Zorzini V., Voorneveld J., Ariza A.,
RA Honarmand Ebrahimi K., Reber J.M., Krassnig S.C., Ahel D.,
RA van der Marel G.A., Mangerich A., McCullagh J.S.O., Filippov D.V., Ahel I.;
RT "Mechanistic insights into the three steps of poly(ADP-ribosylation)
RT reversal.";
RL Nat. Commun. 12:4581-4581(2021).
RN [32]
RP INVOLVEMENT IN CONDSIAS, VARIANTS CONDSIAS ASN-34; PRO-79; 106-GLN--SER-363
RP DEL; LEU-177 AND 334-GLN--SER-363 DEL, AND CHARACTERIZATION OF VARIANTS
RP CONDSIAS PRO-79; 106-GLN--SER-363 DEL AND 334-GLN--SER-363 DEL.
RX PubMed=30100084; DOI=10.1016/j.ajhg.2018.07.010;
RA Ghosh S.G., Becker K., Huang H., Dixon-Salazar T., Chai G., Salpietro V.,
RA Al-Gazali L., Waisfisz Q., Wang H., Vaux K.K., Stanley V., Manole A.,
RA Akpulat U., Weiss M.M., Efthymiou S., Hanna M.G., Minetti C., Striano P.,
RA Pisciotta L., De Grandis E., Altmueller J., Nuernberg P., Thiele H.,
RA Yis U., Okur T.D., Polat A.I., Amiri N., Doosti M., Karimani E.G.,
RA Toosi M.B., Haddad G., Karakaya M., Wirth B., van Hagen J.M., Wolf N.I.,
RA Maroofian R., Houlden H., Cirak S., Gleeson J.G.;
RT "Biallelic mutations in ADPRHL2, encoding ADP-ribosylhydrolase 3, lead to a
RT degenerative pediatric stress-induced epileptic ataxia syndrome.";
RL Am. J. Hum. Genet. 103:431-439(2018).
RN [33]
RP INVOLVEMENT IN CONDSIAS, VARIANTS CONDSIAS 248-LYS-ILE-249 DELINS ASN;
RP GLY-335 AND 346-TYR--SER-363 DEL, FUNCTION, AND CHARACTERIZATION OF
RP VARIANTS CONDSIAS 248-LYS-ILE-249 DELINS ASN AND GLY-335.
RX PubMed=30401461; DOI=10.1016/j.ajhg.2018.10.005;
RA Danhauser K., Alhaddad B., Makowski C., Piekutowska-Abramczuk D., Syrbe S.,
RA Gomez-Ospina N., Manning M.A., Kostera-Pruszczyk A., Krahn-Peper C.,
RA Berutti R., Kovacs-Nagy R., Gusic M., Graf E., Laugwitz L., Roeblitz M.,
RA Wroblewski A., Hartmann H., Das A.M., Bueltmann E., Fang F., Xu M.,
RA Schatz U.A., Karall D., Zellner H., Haberlandt E., Feichtinger R.G.,
RA Mayr J.A., Meitinger T., Prokisch H., Strom T.M., Ploski R., Hoffmann G.F.,
RA Pronicki M., Bonnen P.E., Morlot S., Haack T.B.;
RT "Bi-allelic ADPRHL2 mutations cause neurodegeneration with developmental
RT delay, ataxia, and axonal neuropathy.";
RL Am. J. Hum. Genet. 103:817-825(2018).
RN [34]
RP CHARACTERIZATION OF VARIANTS CONDSIAS PHE-26 AND GLY-335, FUNCTION,
RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF ASP-77 AND ASP-78.
RX PubMed=34479984; DOI=10.26508/lsa.202101057;
RA Beijer D., Agnew T., Rack J.G.M., Prokhorova E., Deconinck T.,
RA Ceulemans B., Peric S., Milic Rasic V., De Jonghe P., Ahel I., Baets J.;
RT "Biallelic ADPRHL2 mutations in complex neuropathy affect ADP ribosylation
RT and DNA damage response.";
RL Life. Sci Alliance 4:0-0(2021).
RN [35]
RP VARIANT CONDSIAS PHE-26, FUNCTION, AND MUTAGENESIS OF ASP-77 AND ASP-78.
RX PubMed=34019811; DOI=10.1016/j.molcel.2021.04.028;
RA Prokhorova E., Agnew T., Wondisford A.R., Tellier M., Kaminski N.,
RA Beijer D., Holder J., Groslambert J., Suskiewicz M.J., Zhu K., Reber J.M.,
RA Krassnig S.C., Palazzo L., Murphy S., Nielsen M.L., Mangerich A., Ahel D.,
RA Baets J., O'Sullivan R.J., Ahel I.;
RT "Unrestrained poly-ADP-ribosylation provides insights into chromatin
RT regulation and human disease.";
RL Mol. Cell 81:2640-2655.e8(2021).
CC -!- FUNCTION: ADP-ribosylhydrolase that preferentially hydrolyzes the
CC scissile alpha-O-linkage attached to the anomeric C1'' position of ADP-
CC ribose and acts on different substrates, such as proteins ADP-
CC ribosylated on serine and threonine, free poly(ADP-ribose) and O-
CC acetyl-ADP-D-ribose (PubMed:21498885, PubMed:30830864, PubMed:33769608,
CC PubMed:30045870, PubMed:29907568, PubMed:34321462, PubMed:30401461,
CC PubMed:33186521, PubMed:34019811, PubMed:33894202, PubMed:34479984).
CC Specifically acts as a serine mono-ADP-ribosylhydrolase by mediating
CC the removal of mono-ADP-ribose attached to serine residues on proteins,
CC thereby playing a key role in DNA damage response (PubMed:28650317,
CC PubMed:29234005, PubMed:33186521, PubMed:30045870, PubMed:34019811).
CC Serine ADP-ribosylation of proteins constitutes the primary form of
CC ADP-ribosylation of proteins in response to DNA damage
CC (PubMed:29480802, PubMed:33186521). Does not hydrolyze ADP-ribosyl-
CC arginine, -cysteine, -diphthamide, or -asparagine bonds
CC (PubMed:16278211, PubMed:33769608). Also able to degrade protein free
CC poly(ADP-ribose), which is synthesized in response to DNA damage: free
CC poly(ADP-ribose) acts as a potent cell death signal and its degradation
CC by ADPRHL2 protects cells from poly(ADP-ribose)-dependent cell death, a
CC process named parthanatos (PubMed:16278211). Also hydrolyzes free
CC poly(ADP-ribose) in mitochondria (PubMed:22433848). Specifically
CC digests O-acetyl-ADP-D-ribose, a product of deacetylation reactions
CC catalyzed by sirtuins (PubMed:17075046, PubMed:21498885). Specifically
CC degrades 1''-O-acetyl-ADP-D-ribose isomer, rather than 2''-O-acetyl-
CC ADP-D-ribose or 3''-O-acetyl-ADP-D-ribose isomers (PubMed:21498885).
CC {ECO:0000269|PubMed:16278211, ECO:0000269|PubMed:17075046,
CC ECO:0000269|PubMed:21498885, ECO:0000269|PubMed:22433848,
CC ECO:0000269|PubMed:28650317, ECO:0000269|PubMed:29234005,
CC ECO:0000269|PubMed:29480802, ECO:0000269|PubMed:29907568,
CC ECO:0000269|PubMed:30045870, ECO:0000269|PubMed:30401461,
CC ECO:0000269|PubMed:30830864, ECO:0000269|PubMed:33186521,
CC ECO:0000269|PubMed:33769608, ECO:0000269|PubMed:33894202,
CC ECO:0000269|PubMed:34019811, ECO:0000269|PubMed:34321462,
CC ECO:0000269|PubMed:34479984}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=[(1''->2')-ADP-alpha-D-ribose](n) + H2O = [(1''->2')-ADP-
CC alpha-D-ribose](n-1) + ADP-D-ribose; Xref=Rhea:RHEA:52216, Rhea:RHEA-
CC COMP:16922, Rhea:RHEA-COMP:16923, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:57967, ChEBI:CHEBI:142512; EC=3.2.1.143;
CC Evidence={ECO:0000269|PubMed:16278211, ECO:0000269|PubMed:17075046,
CC ECO:0000269|PubMed:22433848};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:52217;
CC Evidence={ECO:0000269|PubMed:16278211, ECO:0000269|PubMed:17075046,
CC ECO:0000269|PubMed:22433848};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1''-O-acetyl-ADP-alpha-D-ribose + H2O = acetate + ADP-D-ribose
CC + H(+); Xref=Rhea:RHEA:58112, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30089, ChEBI:CHEBI:57967, ChEBI:CHEBI:142511;
CC Evidence={ECO:0000269|PubMed:17075046, ECO:0000269|PubMed:21498885};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58113;
CC Evidence={ECO:0000269|PubMed:17075046, ECO:0000269|PubMed:21498885};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + O-(ADP-D-ribosyl)-L-seryl-[protein] = ADP-D-ribose + L-
CC seryl-[protein]; Xref=Rhea:RHEA:58256, Rhea:RHEA-COMP:9863,
CC Rhea:RHEA-COMP:15091, ChEBI:CHEBI:15377, ChEBI:CHEBI:29999,
CC ChEBI:CHEBI:57967, ChEBI:CHEBI:142556;
CC Evidence={ECO:0000269|PubMed:28650317, ECO:0000269|PubMed:29234005,
CC ECO:0000269|PubMed:33186521};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58257;
CC Evidence={ECO:0000269|PubMed:28650317, ECO:0000269|PubMed:29234005,
CC ECO:0000269|PubMed:33186521};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=alpha-NAD(+) + H2O = ADP-D-ribose + H(+) + nicotinamide;
CC Xref=Rhea:RHEA:68792, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:17154, ChEBI:CHEBI:57967, ChEBI:CHEBI:77017;
CC Evidence={ECO:0000269|PubMed:31599159, ECO:0000269|PubMed:34321462};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:16278211, ECO:0000269|PubMed:17075046,
CC ECO:0000269|PubMed:17327674, ECO:0000269|PubMed:29907568,
CC ECO:0000269|PubMed:30045870, ECO:0000269|PubMed:33894202};
CC Note=Binds 2 magnesium ions per subunit. {ECO:0000269|PubMed:16278211,
CC ECO:0000269|PubMed:17327674, ECO:0000269|PubMed:29907568,
CC ECO:0000269|PubMed:30045870, ECO:0000269|PubMed:33894202};
CC -!- ACTIVITY REGULATION: The protein undergoes a dramatic conformational
CC switch from closed to open states upon substrate-binding, which enables
CC specific substrate recognition for the 1''-O-linkage (PubMed:29907568,
CC PubMed:34321462). The glutamate flap (Glu-41) blocks substrate entrance
CC to Mg(2+) in the unliganded closed state (PubMed:30045870,
CC PubMed:29907568, PubMed:34321462). In presence of substrate, Glu-41 is
CC ejected from the active site: this closed-to-open transition
CC significantly widens the substrate-binding channel and precisely
CC positions the scissile 1''-O-linkage for cleavage while securing
CC tightly 2'- and 3'-hydroxyls of ADP-ribose (PubMed:30045870,
CC PubMed:29907568, PubMed:34321462). {ECO:0000269|PubMed:29907568,
CC ECO:0000269|PubMed:30045870, ECO:0000269|PubMed:34321462}.
CC -!- SUBUNIT: Monomer. {ECO:0000269|PubMed:16511307,
CC ECO:0000269|PubMed:17015823}.
CC -!- INTERACTION:
CC Q9NX46; Q9NQX1-2: PRDM5; NbExp=3; IntAct=EBI-718580, EBI-12859340;
CC Q9NX46; O95271: TNKS; NbExp=3; IntAct=EBI-718580, EBI-1105254;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:17991898,
CC ECO:0000269|PubMed:34479984}. Cytoplasm {ECO:0000269|PubMed:16278211,
CC ECO:0000269|PubMed:34479984}. Chromosome {ECO:0000269|PubMed:30045870}.
CC Mitochondrion matrix {ECO:0000269|PubMed:17991898,
CC ECO:0000269|PubMed:34479984, ECO:0000305|PubMed:22433848}.
CC Note=Recruited to DNA lesion regions following DNA damage; ADP-D-
CC ribose-recognition is required for recruitment to DNA damage sites.
CC {ECO:0000269|PubMed:30045870}.
CC -!- TISSUE SPECIFICITY: Ubiquitous (PubMed:16278211). Expressed in skin
CC fibroblasts (PubMed:30830864). {ECO:0000269|PubMed:16278211,
CC ECO:0000269|PubMed:30830864}.
CC -!- DISEASE: Neurodegeneration, childhood-onset, stress-induced, with
CC variable ataxia and seizures (CONDSIAS) [MIM:618170]: An autosomal
CC recessive neurodegenerative disorder characterized by pediatric onset
CC of progressive brain atrophy, developmental regression, and seizures in
CC association with periods of stress, such as infections.
CC {ECO:0000269|PubMed:30100084, ECO:0000269|PubMed:30401461,
CC ECO:0000269|PubMed:30830864, ECO:0000269|PubMed:34019811,
CC ECO:0000269|PubMed:34479984}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the ADP-ribosylglycohydrolase family.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAK14922.1; Type=Frameshift; Evidence={ECO:0000305};
CC ---------------------------------------------------------------------------
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DR EMBL; AJ313333; CAC85940.1; -; Genomic_DNA.
DR EMBL; AJ427295; CAD20316.1; -; mRNA.
DR EMBL; AF212236; AAK14922.1; ALT_FRAME; mRNA.
DR EMBL; AK000453; BAA91174.1; -; mRNA.
DR EMBL; CR457237; CAG33518.1; -; mRNA.
DR EMBL; AK223037; BAD96757.1; -; mRNA.
DR EMBL; AL138787; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC014169; AAH14169.1; -; mRNA.
DR CCDS; CCDS402.1; -.
DR RefSeq; NP_060295.1; NM_017825.2.
DR PDB; 2FOZ; X-ray; 1.60 A; A=19-363.
DR PDB; 2FP0; X-ray; 2.05 A; A/B=19-363.
DR PDB; 2G4K; X-ray; 1.82 A; A=18-363.
DR PDB; 5ZQY; X-ray; 1.58 A; A=19-363.
DR PDB; 6D36; X-ray; 1.70 A; A/B/C/D=1-363.
DR PDB; 6D3A; X-ray; 1.60 A; A/B/C/D=1-363.
DR PDB; 7AKR; X-ray; 1.95 A; AAA/BBB/CCC/DDD=19-363.
DR PDB; 7AKS; X-ray; 1.86 A; AAA/CCC/EEE/GGG=19-363.
DR PDB; 7ARW; X-ray; 1.31 A; A/B=19-363.
DR PDB; 7L9F; X-ray; 1.75 A; A/B/C/D=1-363.
DR PDB; 7L9H; X-ray; 1.85 A; A/B/C/D=1-363.
DR PDB; 7L9I; X-ray; 1.80 A; A/B/C/D=1-363.
DR PDBsum; 2FOZ; -.
DR PDBsum; 2FP0; -.
DR PDBsum; 2G4K; -.
DR PDBsum; 5ZQY; -.
DR PDBsum; 6D36; -.
DR PDBsum; 6D3A; -.
DR PDBsum; 7AKR; -.
DR PDBsum; 7AKS; -.
DR PDBsum; 7ARW; -.
DR PDBsum; 7L9F; -.
DR PDBsum; 7L9H; -.
DR PDBsum; 7L9I; -.
DR AlphaFoldDB; Q9NX46; -.
DR SMR; Q9NX46; -.
DR BioGRID; 120276; 37.
DR IntAct; Q9NX46; 9.
DR STRING; 9606.ENSP00000362273; -.
DR ChEMBL; CHEMBL4295963; -.
DR GlyGen; Q9NX46; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q9NX46; -.
DR MetOSite; Q9NX46; -.
DR PhosphoSitePlus; Q9NX46; -.
DR BioMuta; ADPRHL2; -.
DR DMDM; 74753038; -.
DR EPD; Q9NX46; -.
DR jPOST; Q9NX46; -.
DR MassIVE; Q9NX46; -.
DR MaxQB; Q9NX46; -.
DR PaxDb; Q9NX46; -.
DR PeptideAtlas; Q9NX46; -.
DR PRIDE; Q9NX46; -.
DR ProteomicsDB; 83037; -.
DR TopDownProteomics; Q9NX46; -.
DR Antibodypedia; 17409; 113 antibodies from 22 providers.
DR DNASU; 54936; -.
DR Ensembl; ENST00000373178.5; ENSP00000362273.4; ENSG00000116863.11.
DR GeneID; 54936; -.
DR KEGG; hsa:54936; -.
DR MANE-Select; ENST00000373178.5; ENSP00000362273.4; NM_017825.3; NP_060295.1.
DR UCSC; uc001bzt.4; human.
DR CTD; 54936; -.
DR DisGeNET; 54936; -.
DR GeneCards; ADPRS; -.
DR HGNC; HGNC:21304; ADPRS.
DR HPA; ENSG00000116863; Low tissue specificity.
DR MalaCards; ADPRS; -.
DR MIM; 610624; gene.
DR MIM; 618170; phenotype.
DR neXtProt; NX_Q9NX46; -.
DR OpenTargets; ENSG00000116863; -.
DR VEuPathDB; HostDB:ENSG00000116863; -.
DR eggNOG; ENOG502QUER; Eukaryota.
DR GeneTree; ENSGT00390000015369; -.
DR HOGENOM; CLU_024566_6_0_1; -.
DR InParanoid; Q9NX46; -.
DR OMA; IPPSWEQ; -.
DR OrthoDB; 988788at2759; -.
DR PhylomeDB; Q9NX46; -.
DR TreeFam; TF324754; -.
DR BRENDA; 3.2.1.143; 2681.
DR PathwayCommons; Q9NX46; -.
DR Reactome; R-HSA-110362; POLB-Dependent Long Patch Base Excision Repair.
DR SignaLink; Q9NX46; -.
DR BioGRID-ORCS; 54936; 60 hits in 1083 CRISPR screens.
DR EvolutionaryTrace; Q9NX46; -.
DR GeneWiki; ADPRHL2; -.
DR GenomeRNAi; 54936; -.
DR Pharos; Q9NX46; Tbio.
DR PRO; PR:Q9NX46; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; Q9NX46; protein.
DR Bgee; ENSG00000116863; Expressed in oviduct epithelium and 185 other tissues.
DR Genevisible; Q9NX46; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0016604; C:nuclear body; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0090734; C:site of DNA damage; IDA:UniProtKB.
DR GO; GO:0140292; F:ADP-ribosylserine hydrolase activity; IDA:UniProtKB.
DR GO; GO:0004553; F:hydrolase activity, hydrolyzing O-glycosyl compounds; IDA:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR GO; GO:0061463; F:O-acetyl-ADP-ribose deacetylase activity; IDA:UniProtKB.
DR GO; GO:0004649; F:poly(ADP-ribose) glycohydrolase activity; IDA:UniProtKB.
DR GO; GO:0006287; P:base-excision repair, gap-filling; TAS:Reactome.
DR GO; GO:0071451; P:cellular response to superoxide; IMP:UniProtKB.
DR GO; GO:0006281; P:DNA repair; IMP:UniProtKB.
DR GO; GO:0060546; P:negative regulation of necroptotic process; ISS:UniProtKB.
DR GO; GO:0140290; P:peptidyl-serine ADP-deribosylation; IDA:UniProtKB.
DR Gene3D; 1.10.4080.10; -; 1.
DR InterPro; IPR005502; Ribosyl_crysJ1.
DR InterPro; IPR036705; Ribosyl_crysJ1_sf.
DR Pfam; PF03747; ADP_ribosyl_GH; 1.
DR SUPFAM; SSF101478; SSF101478; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Chromosome; Cytoplasm; Disease variant; DNA damage;
KW DNA repair; Hydrolase; Magnesium; Metal-binding; Mitochondrion;
KW Neurodegeneration; Nucleus; Phosphoprotein; Reference proteome.
FT CHAIN 1..363
FT /note="ADP-ribosylhydrolase ARH3"
FT /id="PRO_0000277613"
FT BINDING 41
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:21892188,
FT ECO:0000269|PubMed:29907568, ECO:0000269|PubMed:30045870,
FT ECO:0007744|PDB:5ZQY, ECO:0007744|PDB:6D36,
FT ECO:0007744|PDB:6D3A"
FT BINDING 76
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:21892188,
FT ECO:0000269|PubMed:29907568, ECO:0000269|PubMed:30045870,
FT ECO:0000269|PubMed:33894202, ECO:0007744|PDB:5ZQY,
FT ECO:0007744|PDB:6D36, ECO:0007744|PDB:6D3A,
FT ECO:0007744|PDB:7L9I"
FT BINDING 77
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:21892188,
FT ECO:0000269|PubMed:29907568, ECO:0000269|PubMed:30045870,
FT ECO:0000269|PubMed:33894202, ECO:0000269|PubMed:34321462,
FT ECO:0007744|PDB:5ZQY, ECO:0007744|PDB:6D36,
FT ECO:0007744|PDB:6D3A, ECO:0007744|PDB:7AKR,
FT ECO:0007744|PDB:7AKS, ECO:0007744|PDB:7ARW,
FT ECO:0007744|PDB:7L9I"
FT BINDING 77
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:29907568,
FT ECO:0000269|PubMed:30045870, ECO:0007744|PDB:5ZQY,
FT ECO:0007744|PDB:6D36, ECO:0007744|PDB:6D3A"
FT BINDING 78
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:21892188,
FT ECO:0000269|PubMed:29907568, ECO:0000269|PubMed:30045870,
FT ECO:0000269|PubMed:33894202, ECO:0000269|PubMed:34321462,
FT ECO:0007744|PDB:5ZQY, ECO:0007744|PDB:6D36,
FT ECO:0007744|PDB:6D3A, ECO:0007744|PDB:7AKR,
FT ECO:0007744|PDB:7AKS, ECO:0007744|PDB:7ARW,
FT ECO:0007744|PDB:7L9I"
FT BINDING 78
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:34321462,
FT ECO:0007744|PDB:7ARW"
FT BINDING 146..152
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:29907568,
FT ECO:0000269|PubMed:30045870, ECO:0007744|PDB:5ZQY,
FT ECO:0007744|PDB:6D36, ECO:0007744|PDB:6D3A"
FT BINDING 182
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:29907568,
FT ECO:0000269|PubMed:30045870, ECO:0007744|PDB:5ZQY,
FT ECO:0007744|PDB:6D36, ECO:0007744|PDB:6D3A"
FT BINDING 235
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:29907568,
FT ECO:0007744|PDB:6D36, ECO:0007744|PDB:6D3A"
FT BINDING 271
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:29907568,
FT ECO:0007744|PDB:6D36, ECO:0007744|PDB:6D3A"
FT BINDING 314
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:21892188,
FT ECO:0000269|PubMed:29907568, ECO:0000269|PubMed:30045870,
FT ECO:0000269|PubMed:33894202, ECO:0000269|PubMed:34321462,
FT ECO:0007744|PDB:5ZQY, ECO:0007744|PDB:6D36,
FT ECO:0007744|PDB:6D3A, ECO:0007744|PDB:7AKR,
FT ECO:0007744|PDB:7AKS, ECO:0007744|PDB:7ARW,
FT ECO:0007744|PDB:7L9H"
FT BINDING 316
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:21892188,
FT ECO:0000269|PubMed:29907568, ECO:0000269|PubMed:30045870,
FT ECO:0000269|PubMed:33894202, ECO:0000269|PubMed:34321462,
FT ECO:0007744|PDB:5ZQY, ECO:0007744|PDB:6D36,
FT ECO:0007744|PDB:6D3A, ECO:0007744|PDB:7AKR,
FT ECO:0007744|PDB:7AKS, ECO:0007744|PDB:7ARW,
FT ECO:0007744|PDB:7L9I"
FT BINDING 316
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:21892188,
FT ECO:0000269|PubMed:29907568, ECO:0000269|PubMed:30045870,
FT ECO:0000269|PubMed:33894202, ECO:0000269|PubMed:34321462,
FT ECO:0007744|PDB:5ZQY, ECO:0007744|PDB:6D36,
FT ECO:0007744|PDB:6D3A, ECO:0007744|PDB:7AKR,
FT ECO:0007744|PDB:7AKS, ECO:0007744|PDB:7ARW,
FT ECO:0007744|PDB:7L9H"
FT BINDING 317
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:21892188,
FT ECO:0000269|PubMed:29907568, ECO:0000269|PubMed:30045870,
FT ECO:0000269|PubMed:33894202, ECO:0007744|PDB:5ZQY,
FT ECO:0007744|PDB:6D36, ECO:0007744|PDB:6D3A,
FT ECO:0007744|PDB:7L9H"
FT SITE 41
FT /note="Glutamate flap"
FT /evidence="ECO:0000269|PubMed:29907568,
FT ECO:0000269|PubMed:30045870"
FT MOD_RES 64
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VARIANT 26
FT /note="C -> F (in CONDSIAS; unknown pathological
FT significance; reduced protein abundance; increased levels
FT of ADP-ribose; May result in protein misfolding or
FT aggregation)"
FT /evidence="ECO:0000269|PubMed:34019811,
FT ECO:0000269|PubMed:34479984"
FT /id="VAR_085654"
FT VARIANT 34
FT /note="D -> N (in CONDSIAS; unknown pathological
FT significance; dbSNP:rs1557732234)"
FT /evidence="ECO:0000269|PubMed:30100084"
FT /id="VAR_081264"
FT VARIANT 79
FT /note="T -> P (in CONDSIAS; severely reduced protein levels
FT in patient fibroblasts; decreased stability and reduced Tm;
FT reduced alpha-helix content and altered secondary structure
FT detected by circular dichroism spectroscopy;
FT dbSNP:rs1557733311)"
FT /evidence="ECO:0000269|PubMed:30100084"
FT /id="VAR_081265"
FT VARIANT 106..363
FT /note="Missing (in CONDSIAS; no detectable protein in
FT patient fibroblasts)"
FT /evidence="ECO:0000269|PubMed:30100084"
FT /id="VAR_081266"
FT VARIANT 177
FT /note="S -> L (in CONDSIAS; unknown pathological
FT significance; dbSNP:rs200626873)"
FT /evidence="ECO:0000269|PubMed:30100084"
FT /id="VAR_081267"
FT VARIANT 209
FT /note="E -> K (in dbSNP:rs2236387)"
FT /evidence="ECO:0000269|Ref.5"
FT /id="VAR_030579"
FT VARIANT 248..249
FT /note="KI -> N (in CONDSIAS; no detectable protein levels
FT in patient fibroblasts)"
FT /evidence="ECO:0000269|PubMed:30401461"
FT /id="VAR_081268"
FT VARIANT 334..363
FT /note="Missing (in CONDSIAS; no detectable protein in
FT patient fibroblasts)"
FT /evidence="ECO:0000269|PubMed:30100084"
FT /id="VAR_081269"
FT VARIANT 335
FT /note="V -> G (in CONDSIAS; unknown pathological
FT significance; results in accumulation of poly(ADP-ribose)
FT in the nucleus of patient cells after exposure to H(2)O(2);
FT reduced protein abundance in fibroblasts; localization to
FT the cytoplasm in fibroblasts; no effect on hydrolase
FT activity in vitro; may result in reduced protein stability;
FT dbSNP:rs201735454)"
FT /evidence="ECO:0000269|PubMed:30401461,
FT ECO:0000269|PubMed:34479984"
FT /id="VAR_081270"
FT VARIANT 346..363
FT /note="Missing (in CONDSIAS; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:30401461"
FT /id="VAR_081271"
FT MUTAGEN 34
FT /note="D->G: Reduces hydrolase activity."
FT /evidence="ECO:0000269|PubMed:34321462"
FT MUTAGEN 41
FT /note="E->A,Q: Significant loss of activity. Does not
FT affect recruitment to DNA lesion regions following DNA
FT damage. Strongly reduced ability to hydrolyze proteins ADP-
FT ribosylated on serine."
FT /evidence="ECO:0000269|PubMed:17015823,
FT ECO:0000269|PubMed:29234005, ECO:0000269|PubMed:30045870,
FT ECO:0000269|PubMed:34321462"
FT MUTAGEN 76
FT /note="T->R: Abolishes hydrolase activity."
FT /evidence="ECO:0000269|PubMed:34321462"
FT MUTAGEN 77..78
FT /note="DD->AA: Retains ability to bind proteins ADP-
FT ribosylated on serine but is unable to hydrolyze them."
FT /evidence="ECO:0000269|PubMed:29234005"
FT MUTAGEN 77..78
FT /note="DD->NN: Complete loss of activity."
FT /evidence="ECO:0000269|PubMed:16278211,
FT ECO:0000269|PubMed:17075046, ECO:0000269|PubMed:28650317"
FT MUTAGEN 77
FT /note="D->N,A: Complete loss of activity. Abolishes Mg(2+)
FT binding. Retains ability to bind ADP-ribose. Does not
FT affect recruitment to DNA lesion regions following DNA
FT damage. Strongly reduced ability to hydrolyze proteins ADP-
FT ribosylated on serine."
FT /evidence="ECO:0000269|PubMed:17015823,
FT ECO:0000269|PubMed:28650317, ECO:0000269|PubMed:29234005,
FT ECO:0000269|PubMed:30045870, ECO:0000269|PubMed:31599159,
FT ECO:0000269|PubMed:33769608, ECO:0000269|PubMed:33894202,
FT ECO:0000269|PubMed:34019811, ECO:0000269|PubMed:34321462,
FT ECO:0000269|PubMed:34479984"
FT MUTAGEN 78
FT /note="D->A: Abolishes hydrolase activity."
FT /evidence="ECO:0000269|PubMed:33894202"
FT MUTAGEN 78
FT /note="D->N: Complete loss of activity."
FT /evidence="ECO:0000269|PubMed:28650317,
FT ECO:0000269|PubMed:31599159, ECO:0000269|PubMed:33769608,
FT ECO:0000269|PubMed:34019811, ECO:0000269|PubMed:34321462,
FT ECO:0000269|PubMed:34479984"
FT MUTAGEN 115
FT /note="G->D: Abolished ability to bind and hydrolyze
FT proteins ADP-ribosylated on serine. No effect on hydrolase
FT activity."
FT /evidence="ECO:0000269|PubMed:29234005,
FT ECO:0000269|PubMed:34321462"
FT MUTAGEN 143
FT /note="F->L: Abolishes hydrolase activity."
FT /evidence="ECO:0000269|PubMed:34321462"
FT MUTAGEN 148
FT /note="S->A: Complete loss of activity. Abolished
FT recruitment to DNA lesion regions following DNA damage.
FT Abolished ability to hydrolyze proteins ADP-ribosylated on
FT serine."
FT /evidence="ECO:0000269|PubMed:17015823,
FT ECO:0000269|PubMed:29234005, ECO:0000269|PubMed:30045870,
FT ECO:0000269|PubMed:34321462"
FT MUTAGEN 149
FT /note="Y->A: Significant loss of activity. Abolished
FT recruitment to DNA lesion regions following DNA damage.
FT Abolished ability to hydrolyze proteins ADP-ribosylated on
FT serine."
FT /evidence="ECO:0000269|PubMed:17015823,
FT ECO:0000269|PubMed:29234005, ECO:0000269|PubMed:30045870"
FT MUTAGEN 149
FT /note="Y->L: No effect on hydrolase activity."
FT /evidence="ECO:0000269|PubMed:34321462"
FT MUTAGEN 150
FT /note="G->E: Reduces hydrolase activity."
FT /evidence="ECO:0000269|PubMed:34321462"
FT MUTAGEN 151
FT /note="N->A: Partial loss of activity."
FT /evidence="ECO:0000269|PubMed:17015823"
FT MUTAGEN 182
FT /note="H->Q,A: Complete loss of activity. Abolished
FT recruitment to DNA lesion regions following DNA damage.
FT Abolished ability to hydrolyze proteins ADP-ribosylated on
FT serine."
FT /evidence="ECO:0000269|PubMed:17015823,
FT ECO:0000269|PubMed:29234005, ECO:0000269|PubMed:30045870"
FT MUTAGEN 185
FT /note="S->P: No effect on hydrolase activity."
FT /evidence="ECO:0000269|PubMed:34321462"
FT MUTAGEN 186
FT /note="L->V: No effect on hydrolase activity."
FT /evidence="ECO:0000269|PubMed:34321462"
FT MUTAGEN 238..239
FT /note="EE->QQ: Slight reduction in activity toward
FT poly(ADP-ribose). Does not affect ability to degrade O-
FT acetyl-ADP-D-ribose."
FT /evidence="ECO:0000269|PubMed:16278211,
FT ECO:0000269|PubMed:17075046"
FT MUTAGEN 261..262
FT /note="EE->QQ: Slight reduction in activity toward
FT poly(ADP-ribose). Does not affect ability to degrade O-
FT acetyl-ADP-D-ribose."
FT /evidence="ECO:0000269|PubMed:16278211,
FT ECO:0000269|PubMed:17075046"
FT MUTAGEN 269
FT /note="N->A: No effect on hydrolase activity."
FT /evidence="ECO:0000269|PubMed:34321462"
FT MUTAGEN 270
FT /note="G->C: No effect on hydrolase activity."
FT /evidence="ECO:0000269|PubMed:34321462"
FT MUTAGEN 271
FT /note="I->A: No effect on hydrolase activity."
FT /evidence="ECO:0000269|PubMed:34321462"
FT MUTAGEN 314
FT /note="D->A,E: Complete loss of activity. Abolishes Mg(2+)
FT and ADP-ribose binding. Does not affect recruitment to DNA
FT lesion regions following DNA damage. Retains ability to
FT bind proteins ADP-ribosylated on serine but is unable to
FT hydrolyze them."
FT /evidence="ECO:0000269|PubMed:17015823,
FT ECO:0000269|PubMed:29234005, ECO:0000269|PubMed:29907568,
FT ECO:0000269|PubMed:30045870, ECO:0000269|PubMed:33894202"
FT MUTAGEN 314
FT /note="D->N: Significant loss of activity."
FT /evidence="ECO:0000269|PubMed:17015823"
FT MUTAGEN 316
FT /note="D->A: Abolishes hydrolase activity."
FT /evidence="ECO:0000269|PubMed:33894202"
FT MUTAGEN 317
FT /note="T->A: Complete loss of activity. Does not affect
FT recruitment to DNA lesion regions following DNA damage.
FT Retains ability to bind proteins ADP-ribosylated on serine
FT but is unable to hydrolyze them."
FT /evidence="ECO:0000269|PubMed:17015823,
FT ECO:0000269|PubMed:29234005, ECO:0000269|PubMed:30045870"
FT MUTAGEN 317
FT /note="T->S: Partial loss of activity."
FT /evidence="ECO:0000269|PubMed:17015823"
FT CONFLICT 109
FT /note="K -> E (in Ref. 4; CAG33518)"
FT /evidence="ECO:0000305"
FT HELIX 19..42
FT /evidence="ECO:0007829|PDB:7ARW"
FT HELIX 48..53
FT /evidence="ECO:0007829|PDB:7ARW"
FT HELIX 54..58
FT /evidence="ECO:0007829|PDB:7ARW"
FT STRAND 62..64
FT /evidence="ECO:0007829|PDB:6D3A"
FT HELIX 77..92
FT /evidence="ECO:0007829|PDB:7ARW"
FT HELIX 97..110
FT /evidence="ECO:0007829|PDB:7ARW"
FT TURN 113..115
FT /evidence="ECO:0007829|PDB:5ZQY"
FT HELIX 120..127
FT /evidence="ECO:0007829|PDB:7ARW"
FT HELIX 137..145
FT /evidence="ECO:0007829|PDB:7ARW"
FT HELIX 152..155
FT /evidence="ECO:0007829|PDB:7ARW"
FT HELIX 158..163
FT /evidence="ECO:0007829|PDB:7ARW"
FT HELIX 167..179
FT /evidence="ECO:0007829|PDB:7ARW"
FT HELIX 185..201
FT /evidence="ECO:0007829|PDB:7ARW"
FT HELIX 208..223
FT /evidence="ECO:0007829|PDB:7ARW"
FT HELIX 226..234
FT /evidence="ECO:0007829|PDB:7ARW"
FT HELIX 241..253
FT /evidence="ECO:0007829|PDB:7ARW"
FT STRAND 255..257
FT /evidence="ECO:0007829|PDB:2FOZ"
FT HELIX 260..267
FT /evidence="ECO:0007829|PDB:7ARW"
FT STRAND 270..272
FT /evidence="ECO:0007829|PDB:7ARW"
FT HELIX 273..275
FT /evidence="ECO:0007829|PDB:7ARW"
FT HELIX 277..286
FT /evidence="ECO:0007829|PDB:7ARW"
FT HELIX 300..310
FT /evidence="ECO:0007829|PDB:7ARW"
FT HELIX 315..330
FT /evidence="ECO:0007829|PDB:7ARW"
FT HELIX 332..334
FT /evidence="ECO:0007829|PDB:7ARW"
FT HELIX 337..340
FT /evidence="ECO:0007829|PDB:7ARW"
FT HELIX 346..360
FT /evidence="ECO:0007829|PDB:7ARW"
SQ SEQUENCE 363 AA; 38947 MW; 5FD99F59F27CD29F CRC64;
MAAAAMAAAA GGGAGAARSL SRFRGCLAGA LLGDCVGSFY EAHDTVDLTS VLRHVQSLEP
DPGTPGSERT EALYYTDDTA MARALVQSLL AKEAFDEVDM AHRFAQEYKK DPDRGYGAGV
VTVFKKLLNP KCRDVFEPAR AQFNGKGSYG NGGAMRVAGI SLAYSSVQDV QKFARLSAQL
THASSLGYNG AILQALAVHL ALQGESSSEH FLKQLLGHME DLEGDAQSVL DARELGMEER
PYSSRLKKIG ELLDQASVTR EEVVSELGNG IAAFESVPTA IYCFLRCMEP DPEIPSAFNS
LQRTLIYSIS LGGDTDTIAT MAGAIAGAYY GMDQVPESWQ QSCEGYEETD ILAQSLHRVF
QKS
