Full text data of NGLY1
NGLY1
(PNG1)
[Confidence: low (only semi-automatic identification from reviews)]
Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase; PNGase; hPNGase; 3.5.1.52 (N-glycanase 1; Peptide:N-glycanase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase; PNGase; hPNGase; 3.5.1.52 (N-glycanase 1; Peptide:N-glycanase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q96IV0
ID NGLY1_HUMAN Reviewed; 654 AA.
AC Q96IV0; B4DJE9; Q59FB1; Q6PJD8; Q9BVR8; Q9NR70;
DT 05-SEP-2006, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-DEC-2001, sequence version 1.
DT 22-JAN-2014, entry version 102.
DE RecName: Full=Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase;
DE Short=PNGase;
DE Short=hPNGase;
DE EC=3.5.1.52;
DE AltName: Full=N-glycanase 1;
DE AltName: Full=Peptide:N-glycanase;
GN Name=NGLY1; Synonyms=PNG1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=10831608; DOI=10.1083/jcb.149.5.1039;
RA Suzuki T., Park H., Hollingsworth N.M., Sternglanz R., Lennarz W.J.;
RT "PNG1, a yeast gene encoding a highly conserved peptide:N-glycanase.";
RL J. Cell Biol. 149:1039-1052(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5).
RC TISSUE=Subthalamic nucleus;
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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3), AND
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 4-654 (ISOFORM 2).
RC TISSUE=Lymph, Placenta, and Uterus;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP INTERACTION WITH VCP.
RX PubMed=15362974; DOI=10.1042/BJ20041498;
RA McNeill H., Knebel A., Arthur J.S., Cuenda A., Cohen P.;
RT "A novel UBA and UBX domain protein that binds polyubiquitin and VCP
RT and is a substrate for SAPKs.";
RL Biochem. J. 384:391-400(2004).
RN [7]
RP FUNCTION.
RX PubMed=14749736; DOI=10.1038/sj.emboj.7600090;
RA Blom D., Hirsch C., Stern P., Tortorella D., Ploegh H.L.;
RT "A glycosylated type I membrane protein becomes cytosolic when
RT peptide: N-glycanase is compromised.";
RL EMBO J. 23:650-658(2004).
RN [8]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH RAD23B AND PSMC1.
RX PubMed=15358861; DOI=10.1073/pnas.0405663101;
RA Katiyar S., Li G., Lennarz W.J.;
RT "A complex between peptide:N-glycanase and two proteasome-linked
RT proteins suggests a mechanism for the degradation of misfolded
RT glycoproteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:13774-13779(2004).
RN [9]
RP ENZYME REGULATION.
RX PubMed=15610852; DOI=10.1016/j.chembiol.2004.11.010;
RA Misaghi S., Pacold M.E., Blom D., Ploegh H.L., Korbel G.A.;
RT "Using a small molecule inhibitor of peptide: N-glycanase to probe its
RT role in glycoprotein turnover.";
RL Chem. Biol. 11:1677-1687(2004).
RN [10]
RP INTERACTION WITH DERL1.
RX PubMed=16055502; DOI=10.1091/mbc.E05-04-0345;
RA Katiyar S., Joshi S., Lennarz W.J.;
RT "The retrotranslocation protein derlin-1 binds peptide:N-glycanase to
RT the endoplasmic reticulum.";
RL Mol. Biol. Cell 16:4584-4594(2005).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [12]
RP INVOLVEMENT IN CDG1V.
RX PubMed=22581936; DOI=10.1136/jmedgenet-2012-100819;
RA Need A.C., Shashi V., Hitomi Y., Schoch K., Shianna K.V.,
RA McDonald M.T., Meisler M.H., Goldstein D.B.;
RT "Clinical application of exome sequencing in undiagnosed genetic
RT conditions.";
RL J. Med. Genet. 49:353-361(2012).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 11-109 IN COMPLEX WITH VCP,
RP AND DOMAIN.
RX PubMed=16807242; DOI=10.1074/jbc.M601173200;
RA Allen M.D., Buchberger A., Bycroft M.;
RT "The PUB domain functions as a p97 binding module in human peptide N-
RT glycanase.";
RL J. Biol. Chem. 281:25502-25508(2006).
CC -!- FUNCTION: Specifically deglycosylates the denatured form of N-
CC linked glycoproteins in the cytoplasm and assists their
CC proteasome-mediated degradation. Cleaves the beta-aspartyl-
CC glucosamine (GlcNAc) of the glycan and the amide side chain of
CC Asn, converting Asn to Asp. Prefers proteins containing high-
CC mannose over those bearing complex type oligosaccharides. Can
CC recognize misfolded proteins in the endoplasmic reticulum that are
CC exported to the cytosol to be destroyed and deglycosylate them,
CC while it has no activity toward native proteins. Deglycosylation
CC is a prerequisite for subsequent proteasome-mediated degradation
CC of some, but not all, misfolded glycoproteins.
CC -!- CATALYTIC ACTIVITY: Hydrolysis of an N(4)-(acetyl-beta-D-
CC glucosaminyl)asparagine residue in which the glucosamine residue
CC may be further glycosylated, to yield a (substituted) N-acetyl-
CC beta-D-glucosaminylamine and a peptide containing an aspartate
CC residue.
CC -!- COFACTOR: Binds 1 zinc ion per subunit (By similarity).
CC -!- ENZYME REGULATION: Inhibited by Z-VAD-fmk, a well-known caspase
CC inhibitor, which inhibits enzyme activity through covalent binding
CC of the carbohydrate to the single Cys-306 residue.
CC -!- SUBUNIT: Component of a complex required to couple
CC retrotranslocation, ubiquitination and deglycosylation composed of
CC NGLY1, SAKS1, AMFR, VCP and RAD23B. Interacts with the proteasome
CC components RAD23B and PSMC1. Interacts with directly with VCP.
CC Interacts with DERL1, bringing it close to the endoplasmic
CC reticulum membrane. Interacts with SAKS1.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1;
CC IsoId=Q96IV0-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q96IV0-2; Sequence=VSP_020344;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=Q96IV0-3; Sequence=VSP_020345, VSP_020346;
CC Note=No experimental confirmation available;
CC Name=4;
CC IsoId=Q96IV0-4; Sequence=VSP_020343;
CC Note=No experimental confirmation available;
CC Name=5;
CC IsoId=Q96IV0-5; Sequence=VSP_043501;
CC Note=No experimental confirmation available;
CC -!- DOMAIN: The PUB domain mediates the interaction with VCP.
CC -!- DISEASE: Congenital disorder of glycosylation 1V (CDG1V)
CC [MIM:615273]: A multisystem disorder caused by a defect in
CC glycoprotein biosynthesis and characterized by under-glycosylated
CC serum glycoproteins. Congenital disorders of glycosylation result
CC in a wide variety of clinical features, such as defects in the
CC nervous system development, psychomotor retardation, dysmorphic
CC features, hypotonia, coagulation disorders, and immunodeficiency.
CC The broad spectrum of features reflects the critical role of N-
CC glycoproteins during embryonic development, differentiation, and
CC maintenance of cell functions. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: In case of infection by cytomegaloviruses, it is
CC not essential for degradation of MHC class I heavy chains.
CC -!- SIMILARITY: Belongs to the transglutaminase-like superfamily.
CC PNGase family.
CC -!- SIMILARITY: Contains 1 PAW domain.
CC -!- SIMILARITY: Contains 1 PUB (PUG) domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH17220.1; Type=Erroneous termination; Positions=77; Note=Translated as Glu;
CC Sequence=BAD92786.1; Type=Erroneous initiation;
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AF250924; AAF74720.2; -; mRNA.
DR EMBL; AK296047; BAG58811.1; -; mRNA.
DR EMBL; AB209549; BAD92786.1; ALT_INIT; mRNA.
DR EMBL; AC092798; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC000963; AAH00963.1; -; mRNA.
DR EMBL; BC007226; AAH07226.1; -; mRNA.
DR EMBL; BC017220; AAH17220.1; ALT_SEQ; mRNA.
DR RefSeq; NP_001138765.1; NM_001145293.1.
DR RefSeq; NP_001138766.1; NM_001145294.1.
DR RefSeq; NP_001138767.1; NM_001145295.1.
DR RefSeq; NP_060767.2; NM_018297.3.
DR UniGene; Hs.368960; -.
DR PDB; 2CCQ; X-ray; 1.60 A; A=11-109.
DR PDB; 2CM0; X-ray; 1.90 A; A=11-109.
DR PDBsum; 2CCQ; -.
DR PDBsum; 2CM0; -.
DR ProteinModelPortal; Q96IV0; -.
DR SMR; Q96IV0; 11-109, 167-453, 475-654.
DR IntAct; Q96IV0; 3.
DR MINT; MINT-3054125; -.
DR STRING; 9606.ENSP00000280700; -.
DR PhosphoSite; Q96IV0; -.
DR DMDM; 74732105; -.
DR PaxDb; Q96IV0; -.
DR PRIDE; Q96IV0; -.
DR DNASU; 55768; -.
DR Ensembl; ENST00000280700; ENSP00000280700; ENSG00000151092.
DR Ensembl; ENST00000308710; ENSP00000307980; ENSG00000151092.
DR Ensembl; ENST00000396649; ENSP00000379886; ENSG00000151092.
DR Ensembl; ENST00000417874; ENSP00000389888; ENSG00000151092.
DR Ensembl; ENST00000428257; ENSP00000387430; ENSG00000151092.
DR GeneID; 55768; -.
DR KEGG; hsa:55768; -.
DR UCSC; uc003cdl.3; human.
DR CTD; 55768; -.
DR GeneCards; GC03M025735; -.
DR HGNC; HGNC:17646; NGLY1.
DR HPA; HPA036825; -.
DR MIM; 610661; gene.
DR MIM; 615273; phenotype.
DR neXtProt; NX_Q96IV0; -.
DR PharmGKB; PA38462; -.
DR eggNOG; NOG307426; -.
DR HOGENOM; HOG000247069; -.
DR HOVERGEN; HBG082026; -.
DR InParanoid; Q96IV0; -.
DR KO; K01456; -.
DR OMA; CQNTPET; -.
DR OrthoDB; EOG780RMR; -.
DR PhylomeDB; Q96IV0; -.
DR ChiTaRS; NGLY1; human.
DR EvolutionaryTrace; Q96IV0; -.
DR GeneWiki; NGLY1; -.
DR GenomeRNAi; 55768; -.
DR NextBio; 60817; -.
DR PRO; PR:Q96IV0; -.
DR ArrayExpress; Q96IV0; -.
DR Bgee; Q96IV0; -.
DR CleanEx; HS_NGLY1; -.
DR Genevestigator; Q96IV0; -.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0000224; F:peptide-N4-(N-acetyl-beta-glucosaminyl)asparagine amidase activity; IEA:UniProtKB-EC.
DR GO; GO:0006516; P:glycoprotein catabolic process; IDA:UniProtKB.
DR InterPro; IPR008979; Galactose-bd-like.
DR InterPro; IPR006588; Peptide_N_glycanase_PAW_dom.
DR InterPro; IPR018997; PUB_domain.
DR InterPro; IPR006567; PUG-dom.
DR InterPro; IPR002931; Transglutaminase-like.
DR Pfam; PF04721; DUF750; 1.
DR Pfam; PF09409; PUB; 1.
DR Pfam; PF01841; Transglut_core; 1.
DR SMART; SM00613; PAW; 1.
DR SMART; SM00580; PUG; 1.
DR SMART; SM00460; TGc; 1.
DR SUPFAM; SSF49785; SSF49785; 1.
DR PROSITE; PS51398; PAW; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Congenital disorder of glycosylation; Cytoplasm; Hydrolase;
KW Metal-binding; Polymorphism; Reference proteome; Zinc.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 654 Peptide-N(4)-(N-acetyl-beta-
FT glucosaminyl)asparagine amidase.
FT /FTId=PRO_0000248971.
FT DOMAIN 30 91 PUB.
FT DOMAIN 454 654 PAW.
FT ACT_SITE 309 309 Nucleophile (By similarity).
FT ACT_SITE 336 336 By similarity.
FT ACT_SITE 353 353 By similarity.
FT METAL 250 250 Zinc (By similarity).
FT METAL 253 253 Zinc (By similarity).
FT METAL 283 283 Zinc (By similarity).
FT METAL 286 286 Zinc (By similarity).
FT MOD_RES 2 2 N-acetylalanine.
FT VAR_SEQ 1 523 Missing (in isoform 4).
FT /FTId=VSP_020343.
FT VAR_SEQ 1 43 MAAAALGSSSGSASPAVAELCQNTPETFLEASKLLLTYADN
FT IL -> M (in isoform 5).
FT /FTId=VSP_043501.
FT VAR_SEQ 335 383 DHVWTEVYSPSQQRWLHCDACEDVCDKPLLYEIGWGKKLSY
FT VIAFSKDE -> ELQRTLSLKLTTLKEIGKTFLRISKRQKL
FT IQ (in isoform 2).
FT /FTId=VSP_020344.
FT VAR_SEQ 538 558 VYLARKEGSSFAYISWKFECG -> ITVFTPMLIFLVPLKL
FT FWKQN (in isoform 3).
FT /FTId=VSP_020345.
FT VAR_SEQ 559 654 Missing (in isoform 3).
FT /FTId=VSP_020346.
FT VARIANT 581 581 V -> I (in dbSNP:rs7621398).
FT /FTId=VAR_027385.
FT VARIANT 591 591 Q -> R (in dbSNP:rs7635089).
FT /FTId=VAR_027386.
FT HELIX 15 20
FT HELIX 25 44
FT HELIX 49 52
FT STRAND 53 55
FT HELIX 59 64
FT TURN 65 67
FT HELIX 71 78
FT STRAND 84 88
FT HELIX 95 106
SQ SEQUENCE 654 AA; 74390 MW; 94BD44316EA66AF6 CRC64;
MAAAALGSSS GSASPAVAEL CQNTPETFLE ASKLLLTYAD NILRNPNDEK YRSIRIGNTA
FSTRLLPVRG AVECLFEMGF EEGETHLIFP KKASVEQLQK IRDLIAIERS SRLDGSNKSH
KVKSSQQPAA STQLPTTPSS NPSGLNQHTR NRQGQSSDPP SASTVAADSA ILEVLQSNIQ
HVLVYENPAL QEKALACIPV QELKRKSQEK LSRARKLDKG INISDEDFLL LELLHWFKEE
FFHWVNNVLC SKCGGQTRSR DRSLLPSDDE LKWGAKEVED HYCDACQFSN RFPRYNNPEK
LLETRCGRCG EWANCFTLCC RAVGFEARYV WDYTDHVWTE VYSPSQQRWL HCDACEDVCD
KPLLYEIGWG KKLSYVIAFS KDEVVDVTWR YSCKHEEVIA RRTKVKEALL RDTINGLNKQ
RQLFLSENRR KELLQRIIVE LVEFISPKTP KPGELGGRIS GSVAWRVARG EMGLQRKETL
FIPCENEKIS KQLHLCYNIV KDRYVRVSNN NQTISGWENG VWKMESIFRK VETDWHMVYL
ARKEGSSFAY ISWKFECGSV GLKVDSISIR TSSQTFQTGT VEWKLRSDTA QVELTGDNSL
HSYADFSGAT EVILEAELSR GDGDVAWQHT QLFRQSLNDH EENCLEIIIK FSDL
//
ID NGLY1_HUMAN Reviewed; 654 AA.
AC Q96IV0; B4DJE9; Q59FB1; Q6PJD8; Q9BVR8; Q9NR70;
DT 05-SEP-2006, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-DEC-2001, sequence version 1.
DT 22-JAN-2014, entry version 102.
DE RecName: Full=Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase;
DE Short=PNGase;
DE Short=hPNGase;
DE EC=3.5.1.52;
DE AltName: Full=N-glycanase 1;
DE AltName: Full=Peptide:N-glycanase;
GN Name=NGLY1; Synonyms=PNG1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=10831608; DOI=10.1083/jcb.149.5.1039;
RA Suzuki T., Park H., Hollingsworth N.M., Sternglanz R., Lennarz W.J.;
RT "PNG1, a yeast gene encoding a highly conserved peptide:N-glycanase.";
RL J. Cell Biol. 149:1039-1052(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5).
RC TISSUE=Subthalamic nucleus;
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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3), AND
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 4-654 (ISOFORM 2).
RC TISSUE=Lymph, Placenta, and Uterus;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP INTERACTION WITH VCP.
RX PubMed=15362974; DOI=10.1042/BJ20041498;
RA McNeill H., Knebel A., Arthur J.S., Cuenda A., Cohen P.;
RT "A novel UBA and UBX domain protein that binds polyubiquitin and VCP
RT and is a substrate for SAPKs.";
RL Biochem. J. 384:391-400(2004).
RN [7]
RP FUNCTION.
RX PubMed=14749736; DOI=10.1038/sj.emboj.7600090;
RA Blom D., Hirsch C., Stern P., Tortorella D., Ploegh H.L.;
RT "A glycosylated type I membrane protein becomes cytosolic when
RT peptide: N-glycanase is compromised.";
RL EMBO J. 23:650-658(2004).
RN [8]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH RAD23B AND PSMC1.
RX PubMed=15358861; DOI=10.1073/pnas.0405663101;
RA Katiyar S., Li G., Lennarz W.J.;
RT "A complex between peptide:N-glycanase and two proteasome-linked
RT proteins suggests a mechanism for the degradation of misfolded
RT glycoproteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:13774-13779(2004).
RN [9]
RP ENZYME REGULATION.
RX PubMed=15610852; DOI=10.1016/j.chembiol.2004.11.010;
RA Misaghi S., Pacold M.E., Blom D., Ploegh H.L., Korbel G.A.;
RT "Using a small molecule inhibitor of peptide: N-glycanase to probe its
RT role in glycoprotein turnover.";
RL Chem. Biol. 11:1677-1687(2004).
RN [10]
RP INTERACTION WITH DERL1.
RX PubMed=16055502; DOI=10.1091/mbc.E05-04-0345;
RA Katiyar S., Joshi S., Lennarz W.J.;
RT "The retrotranslocation protein derlin-1 binds peptide:N-glycanase to
RT the endoplasmic reticulum.";
RL Mol. Biol. Cell 16:4584-4594(2005).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [12]
RP INVOLVEMENT IN CDG1V.
RX PubMed=22581936; DOI=10.1136/jmedgenet-2012-100819;
RA Need A.C., Shashi V., Hitomi Y., Schoch K., Shianna K.V.,
RA McDonald M.T., Meisler M.H., Goldstein D.B.;
RT "Clinical application of exome sequencing in undiagnosed genetic
RT conditions.";
RL J. Med. Genet. 49:353-361(2012).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 11-109 IN COMPLEX WITH VCP,
RP AND DOMAIN.
RX PubMed=16807242; DOI=10.1074/jbc.M601173200;
RA Allen M.D., Buchberger A., Bycroft M.;
RT "The PUB domain functions as a p97 binding module in human peptide N-
RT glycanase.";
RL J. Biol. Chem. 281:25502-25508(2006).
CC -!- FUNCTION: Specifically deglycosylates the denatured form of N-
CC linked glycoproteins in the cytoplasm and assists their
CC proteasome-mediated degradation. Cleaves the beta-aspartyl-
CC glucosamine (GlcNAc) of the glycan and the amide side chain of
CC Asn, converting Asn to Asp. Prefers proteins containing high-
CC mannose over those bearing complex type oligosaccharides. Can
CC recognize misfolded proteins in the endoplasmic reticulum that are
CC exported to the cytosol to be destroyed and deglycosylate them,
CC while it has no activity toward native proteins. Deglycosylation
CC is a prerequisite for subsequent proteasome-mediated degradation
CC of some, but not all, misfolded glycoproteins.
CC -!- CATALYTIC ACTIVITY: Hydrolysis of an N(4)-(acetyl-beta-D-
CC glucosaminyl)asparagine residue in which the glucosamine residue
CC may be further glycosylated, to yield a (substituted) N-acetyl-
CC beta-D-glucosaminylamine and a peptide containing an aspartate
CC residue.
CC -!- COFACTOR: Binds 1 zinc ion per subunit (By similarity).
CC -!- ENZYME REGULATION: Inhibited by Z-VAD-fmk, a well-known caspase
CC inhibitor, which inhibits enzyme activity through covalent binding
CC of the carbohydrate to the single Cys-306 residue.
CC -!- SUBUNIT: Component of a complex required to couple
CC retrotranslocation, ubiquitination and deglycosylation composed of
CC NGLY1, SAKS1, AMFR, VCP and RAD23B. Interacts with the proteasome
CC components RAD23B and PSMC1. Interacts with directly with VCP.
CC Interacts with DERL1, bringing it close to the endoplasmic
CC reticulum membrane. Interacts with SAKS1.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1;
CC IsoId=Q96IV0-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q96IV0-2; Sequence=VSP_020344;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=Q96IV0-3; Sequence=VSP_020345, VSP_020346;
CC Note=No experimental confirmation available;
CC Name=4;
CC IsoId=Q96IV0-4; Sequence=VSP_020343;
CC Note=No experimental confirmation available;
CC Name=5;
CC IsoId=Q96IV0-5; Sequence=VSP_043501;
CC Note=No experimental confirmation available;
CC -!- DOMAIN: The PUB domain mediates the interaction with VCP.
CC -!- DISEASE: Congenital disorder of glycosylation 1V (CDG1V)
CC [MIM:615273]: A multisystem disorder caused by a defect in
CC glycoprotein biosynthesis and characterized by under-glycosylated
CC serum glycoproteins. Congenital disorders of glycosylation result
CC in a wide variety of clinical features, such as defects in the
CC nervous system development, psychomotor retardation, dysmorphic
CC features, hypotonia, coagulation disorders, and immunodeficiency.
CC The broad spectrum of features reflects the critical role of N-
CC glycoproteins during embryonic development, differentiation, and
CC maintenance of cell functions. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: In case of infection by cytomegaloviruses, it is
CC not essential for degradation of MHC class I heavy chains.
CC -!- SIMILARITY: Belongs to the transglutaminase-like superfamily.
CC PNGase family.
CC -!- SIMILARITY: Contains 1 PAW domain.
CC -!- SIMILARITY: Contains 1 PUB (PUG) domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH17220.1; Type=Erroneous termination; Positions=77; Note=Translated as Glu;
CC Sequence=BAD92786.1; Type=Erroneous initiation;
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AF250924; AAF74720.2; -; mRNA.
DR EMBL; AK296047; BAG58811.1; -; mRNA.
DR EMBL; AB209549; BAD92786.1; ALT_INIT; mRNA.
DR EMBL; AC092798; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC000963; AAH00963.1; -; mRNA.
DR EMBL; BC007226; AAH07226.1; -; mRNA.
DR EMBL; BC017220; AAH17220.1; ALT_SEQ; mRNA.
DR RefSeq; NP_001138765.1; NM_001145293.1.
DR RefSeq; NP_001138766.1; NM_001145294.1.
DR RefSeq; NP_001138767.1; NM_001145295.1.
DR RefSeq; NP_060767.2; NM_018297.3.
DR UniGene; Hs.368960; -.
DR PDB; 2CCQ; X-ray; 1.60 A; A=11-109.
DR PDB; 2CM0; X-ray; 1.90 A; A=11-109.
DR PDBsum; 2CCQ; -.
DR PDBsum; 2CM0; -.
DR ProteinModelPortal; Q96IV0; -.
DR SMR; Q96IV0; 11-109, 167-453, 475-654.
DR IntAct; Q96IV0; 3.
DR MINT; MINT-3054125; -.
DR STRING; 9606.ENSP00000280700; -.
DR PhosphoSite; Q96IV0; -.
DR DMDM; 74732105; -.
DR PaxDb; Q96IV0; -.
DR PRIDE; Q96IV0; -.
DR DNASU; 55768; -.
DR Ensembl; ENST00000280700; ENSP00000280700; ENSG00000151092.
DR Ensembl; ENST00000308710; ENSP00000307980; ENSG00000151092.
DR Ensembl; ENST00000396649; ENSP00000379886; ENSG00000151092.
DR Ensembl; ENST00000417874; ENSP00000389888; ENSG00000151092.
DR Ensembl; ENST00000428257; ENSP00000387430; ENSG00000151092.
DR GeneID; 55768; -.
DR KEGG; hsa:55768; -.
DR UCSC; uc003cdl.3; human.
DR CTD; 55768; -.
DR GeneCards; GC03M025735; -.
DR HGNC; HGNC:17646; NGLY1.
DR HPA; HPA036825; -.
DR MIM; 610661; gene.
DR MIM; 615273; phenotype.
DR neXtProt; NX_Q96IV0; -.
DR PharmGKB; PA38462; -.
DR eggNOG; NOG307426; -.
DR HOGENOM; HOG000247069; -.
DR HOVERGEN; HBG082026; -.
DR InParanoid; Q96IV0; -.
DR KO; K01456; -.
DR OMA; CQNTPET; -.
DR OrthoDB; EOG780RMR; -.
DR PhylomeDB; Q96IV0; -.
DR ChiTaRS; NGLY1; human.
DR EvolutionaryTrace; Q96IV0; -.
DR GeneWiki; NGLY1; -.
DR GenomeRNAi; 55768; -.
DR NextBio; 60817; -.
DR PRO; PR:Q96IV0; -.
DR ArrayExpress; Q96IV0; -.
DR Bgee; Q96IV0; -.
DR CleanEx; HS_NGLY1; -.
DR Genevestigator; Q96IV0; -.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0000224; F:peptide-N4-(N-acetyl-beta-glucosaminyl)asparagine amidase activity; IEA:UniProtKB-EC.
DR GO; GO:0006516; P:glycoprotein catabolic process; IDA:UniProtKB.
DR InterPro; IPR008979; Galactose-bd-like.
DR InterPro; IPR006588; Peptide_N_glycanase_PAW_dom.
DR InterPro; IPR018997; PUB_domain.
DR InterPro; IPR006567; PUG-dom.
DR InterPro; IPR002931; Transglutaminase-like.
DR Pfam; PF04721; DUF750; 1.
DR Pfam; PF09409; PUB; 1.
DR Pfam; PF01841; Transglut_core; 1.
DR SMART; SM00613; PAW; 1.
DR SMART; SM00580; PUG; 1.
DR SMART; SM00460; TGc; 1.
DR SUPFAM; SSF49785; SSF49785; 1.
DR PROSITE; PS51398; PAW; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Congenital disorder of glycosylation; Cytoplasm; Hydrolase;
KW Metal-binding; Polymorphism; Reference proteome; Zinc.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 654 Peptide-N(4)-(N-acetyl-beta-
FT glucosaminyl)asparagine amidase.
FT /FTId=PRO_0000248971.
FT DOMAIN 30 91 PUB.
FT DOMAIN 454 654 PAW.
FT ACT_SITE 309 309 Nucleophile (By similarity).
FT ACT_SITE 336 336 By similarity.
FT ACT_SITE 353 353 By similarity.
FT METAL 250 250 Zinc (By similarity).
FT METAL 253 253 Zinc (By similarity).
FT METAL 283 283 Zinc (By similarity).
FT METAL 286 286 Zinc (By similarity).
FT MOD_RES 2 2 N-acetylalanine.
FT VAR_SEQ 1 523 Missing (in isoform 4).
FT /FTId=VSP_020343.
FT VAR_SEQ 1 43 MAAAALGSSSGSASPAVAELCQNTPETFLEASKLLLTYADN
FT IL -> M (in isoform 5).
FT /FTId=VSP_043501.
FT VAR_SEQ 335 383 DHVWTEVYSPSQQRWLHCDACEDVCDKPLLYEIGWGKKLSY
FT VIAFSKDE -> ELQRTLSLKLTTLKEIGKTFLRISKRQKL
FT IQ (in isoform 2).
FT /FTId=VSP_020344.
FT VAR_SEQ 538 558 VYLARKEGSSFAYISWKFECG -> ITVFTPMLIFLVPLKL
FT FWKQN (in isoform 3).
FT /FTId=VSP_020345.
FT VAR_SEQ 559 654 Missing (in isoform 3).
FT /FTId=VSP_020346.
FT VARIANT 581 581 V -> I (in dbSNP:rs7621398).
FT /FTId=VAR_027385.
FT VARIANT 591 591 Q -> R (in dbSNP:rs7635089).
FT /FTId=VAR_027386.
FT HELIX 15 20
FT HELIX 25 44
FT HELIX 49 52
FT STRAND 53 55
FT HELIX 59 64
FT TURN 65 67
FT HELIX 71 78
FT STRAND 84 88
FT HELIX 95 106
SQ SEQUENCE 654 AA; 74390 MW; 94BD44316EA66AF6 CRC64;
MAAAALGSSS GSASPAVAEL CQNTPETFLE ASKLLLTYAD NILRNPNDEK YRSIRIGNTA
FSTRLLPVRG AVECLFEMGF EEGETHLIFP KKASVEQLQK IRDLIAIERS SRLDGSNKSH
KVKSSQQPAA STQLPTTPSS NPSGLNQHTR NRQGQSSDPP SASTVAADSA ILEVLQSNIQ
HVLVYENPAL QEKALACIPV QELKRKSQEK LSRARKLDKG INISDEDFLL LELLHWFKEE
FFHWVNNVLC SKCGGQTRSR DRSLLPSDDE LKWGAKEVED HYCDACQFSN RFPRYNNPEK
LLETRCGRCG EWANCFTLCC RAVGFEARYV WDYTDHVWTE VYSPSQQRWL HCDACEDVCD
KPLLYEIGWG KKLSYVIAFS KDEVVDVTWR YSCKHEEVIA RRTKVKEALL RDTINGLNKQ
RQLFLSENRR KELLQRIIVE LVEFISPKTP KPGELGGRIS GSVAWRVARG EMGLQRKETL
FIPCENEKIS KQLHLCYNIV KDRYVRVSNN NQTISGWENG VWKMESIFRK VETDWHMVYL
ARKEGSSFAY ISWKFECGSV GLKVDSISIR TSSQTFQTGT VEWKLRSDTA QVELTGDNSL
HSYADFSGAT EVILEAELSR GDGDVAWQHT QLFRQSLNDH EENCLEIIIK FSDL
//
MIM
610661
*RECORD*
*FIELD* NO
610661
*FIELD* TI
*610661 N-GLYCANASE 1; NGLY1
;;PEPTIDE-N-GLYCANASE 1, S. CEREVISIAE, HOMOLOG OF; PNG1
read more*FIELD* TX
DESCRIPTION
N-glycanase is a highly conserved enzyme that catalyzes deglycosylation
of misfolded N-linked glycoproteins by cleaving the glycan chain before
the proteins are degraded by the proteasome (Zhou et al., 2006).
CLONING
By EST database analysis, Suzuki et al. (2000) identified several
homologs of yeast Png1, including human NGLY1. In yeast, Png1 was
expressed in both the cytoplasm and nucleus.
Suzuki et al. (2003) cloned mouse Ngly1, and by database analysis, they
identified human NGLY1. The deduced 654-amino acid human protein
contains an N-terminal PUB/PUG protein-protein interaction domain and a
central transglutaminase-like motif containing the catalytic triad of
the active site. Mouse and human NGLY1 share 98% identity in these 2
domains. Northern blot analysis detected Ngly1 expression in all mouse
tissues examined, with highest expression in testis.
BIOCHEMICAL FEATURES
Zhou et al. (2006) resolved the crystal structure of the C-terminal
domain of mouse Ngly1 to 2-angstrom resolution. The C-terminal domain
has a beta-sandwich architecture composed of 2 layers containing 9 and 8
antiparallel beta strands, respectively, and 3 additional short helices.
Zhou et al. (2006) identified several solvent-exposed residues involved
in binding the mannose moieties of N-linked oligosaccharide chains.
Biochemical analysis indicated that the C-terminal domain enhances the
catalytic activity of Ngly1.
GENE STRUCTURE
Suzuki et al. (2003) determined that the NGLY1 gene contains 12 exons
and spans about 70 kb. The mouse gene has a similar organization.
MAPPING
By radiation hybrid analysis, Suzuki et al. (2003) mapped the human and
mouse NGLY1 genes to chromosomes 3 and 14, respectively. Database
analysis suggested that the human gene maps to chromosome 3p24.
GENE FUNCTION
Suzuki et al. (2000) found that recombinant yeast Png1 was soluble.
Deletion of Png1 in yeast delayed degradation of a mutant form of
carboxypeptidase Y.
MOLECULAR GENETICS
By whole-exome sequencing in a family in which a child had a congenital
disorder of glycosylation (CDG1V; 615273), Need et al. (2012) found that
the boy was compound heterozygous for 2 mutations in the NGLY1 gene: a
frameshift mutation in exon 12 (610661.0001) inherited from his mother,
and a nonsense mutation in exon 8 (610661.0002) inherited from his
father. Need et al. (2012) compared NGLY1 protein expression in
leukocytes extracted from blood from the patient, his parents, and 3
controls. Both parents showed reduced expression compared with controls,
and the patient had barely discernible levels of NGLY1.
*FIELD* AV
.0001
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Iv (1 family)
NGLY1, 1-BP DEL, 1891C
Using whole-exome sequencing, in a boy with congenital disorder of
glycosylation (CDG1V; 615273) and his parents, Need et al. (2012) found
that the boy was compound heterozygous for 2 mutations in the NGLY1
gene: a frameshift mutation in exon 12 inherited from his mother, and a
nonsense mutation in exon 8 inherited from his father. The frameshift
mutation resulted from a 1-bp deletion (c.1891delC) and the nonsense
mutation (R401X; 610661.0002) resulted from a 1201A-T transversion
(Shashi, 2013).
.0002
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Iv (1 family)
NGLY1, ARG401TER
See 610661.0001, Need et al. (2012), and Shashi, 2013.
*FIELD* RF
1. Need, A. C.; Shashi, V.; Hitomi, Y.; Schoch, K.; Shianna, K. V.;
McDonald, M. T.: Meisler, M. H.; Goldstein, D. B.: Clinical application
of exome sequencing in undiagnosed genetic conditions. J. Med. Genet. 49:
353-361, 2012.
2. Shashi, V.: Personal Communication. Durham, N.C. 6/11/2013.
3. Suzuki, T.; Kwofie, M. A.; Lennarz, W. J.: Ngly1, a mouse gene
encoding a deglycosylating enzyme implicated in proteasomal degradation:
expression, genomic organization, and chromosomal mapping. Biochem.
Biophys. Res. Commun. 304: 326-332, 2003.
4. Suzuki, T.; Park, H.; Hollingsworth, N. M.; Sternglanz, R.; Lennarz,
W. J.: PNG1, a yeast gene encoding a highly conserved peptide:N-glycanase. J.
Cell Biol. 149: 1039-1051, 2000.
5. Zhou, X.; Zhao, G.; Truglio, J. J.; Wang, L.; Li, G.; Lennarz,
W. J.; Schindelin, H.: Structural and biochemical studies of the
C-terminal domain of mouse peptide-N-glycanase identify it as a mannose-binding
module. Proc. Nat. Acad. Sci. 103: 17214-17219, 2006.
*FIELD* CN
Nara Sobreira - updated: 6/12/2013
*FIELD* CD
Patricia A. Hartz: 12/19/2006
*FIELD* ED
carol: 06/12/2013
carol: 6/12/2013
mgross: 12/19/2006
*RECORD*
*FIELD* NO
610661
*FIELD* TI
*610661 N-GLYCANASE 1; NGLY1
;;PEPTIDE-N-GLYCANASE 1, S. CEREVISIAE, HOMOLOG OF; PNG1
read more*FIELD* TX
DESCRIPTION
N-glycanase is a highly conserved enzyme that catalyzes deglycosylation
of misfolded N-linked glycoproteins by cleaving the glycan chain before
the proteins are degraded by the proteasome (Zhou et al., 2006).
CLONING
By EST database analysis, Suzuki et al. (2000) identified several
homologs of yeast Png1, including human NGLY1. In yeast, Png1 was
expressed in both the cytoplasm and nucleus.
Suzuki et al. (2003) cloned mouse Ngly1, and by database analysis, they
identified human NGLY1. The deduced 654-amino acid human protein
contains an N-terminal PUB/PUG protein-protein interaction domain and a
central transglutaminase-like motif containing the catalytic triad of
the active site. Mouse and human NGLY1 share 98% identity in these 2
domains. Northern blot analysis detected Ngly1 expression in all mouse
tissues examined, with highest expression in testis.
BIOCHEMICAL FEATURES
Zhou et al. (2006) resolved the crystal structure of the C-terminal
domain of mouse Ngly1 to 2-angstrom resolution. The C-terminal domain
has a beta-sandwich architecture composed of 2 layers containing 9 and 8
antiparallel beta strands, respectively, and 3 additional short helices.
Zhou et al. (2006) identified several solvent-exposed residues involved
in binding the mannose moieties of N-linked oligosaccharide chains.
Biochemical analysis indicated that the C-terminal domain enhances the
catalytic activity of Ngly1.
GENE STRUCTURE
Suzuki et al. (2003) determined that the NGLY1 gene contains 12 exons
and spans about 70 kb. The mouse gene has a similar organization.
MAPPING
By radiation hybrid analysis, Suzuki et al. (2003) mapped the human and
mouse NGLY1 genes to chromosomes 3 and 14, respectively. Database
analysis suggested that the human gene maps to chromosome 3p24.
GENE FUNCTION
Suzuki et al. (2000) found that recombinant yeast Png1 was soluble.
Deletion of Png1 in yeast delayed degradation of a mutant form of
carboxypeptidase Y.
MOLECULAR GENETICS
By whole-exome sequencing in a family in which a child had a congenital
disorder of glycosylation (CDG1V; 615273), Need et al. (2012) found that
the boy was compound heterozygous for 2 mutations in the NGLY1 gene: a
frameshift mutation in exon 12 (610661.0001) inherited from his mother,
and a nonsense mutation in exon 8 (610661.0002) inherited from his
father. Need et al. (2012) compared NGLY1 protein expression in
leukocytes extracted from blood from the patient, his parents, and 3
controls. Both parents showed reduced expression compared with controls,
and the patient had barely discernible levels of NGLY1.
*FIELD* AV
.0001
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Iv (1 family)
NGLY1, 1-BP DEL, 1891C
Using whole-exome sequencing, in a boy with congenital disorder of
glycosylation (CDG1V; 615273) and his parents, Need et al. (2012) found
that the boy was compound heterozygous for 2 mutations in the NGLY1
gene: a frameshift mutation in exon 12 inherited from his mother, and a
nonsense mutation in exon 8 inherited from his father. The frameshift
mutation resulted from a 1-bp deletion (c.1891delC) and the nonsense
mutation (R401X; 610661.0002) resulted from a 1201A-T transversion
(Shashi, 2013).
.0002
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Iv (1 family)
NGLY1, ARG401TER
See 610661.0001, Need et al. (2012), and Shashi, 2013.
*FIELD* RF
1. Need, A. C.; Shashi, V.; Hitomi, Y.; Schoch, K.; Shianna, K. V.;
McDonald, M. T.: Meisler, M. H.; Goldstein, D. B.: Clinical application
of exome sequencing in undiagnosed genetic conditions. J. Med. Genet. 49:
353-361, 2012.
2. Shashi, V.: Personal Communication. Durham, N.C. 6/11/2013.
3. Suzuki, T.; Kwofie, M. A.; Lennarz, W. J.: Ngly1, a mouse gene
encoding a deglycosylating enzyme implicated in proteasomal degradation:
expression, genomic organization, and chromosomal mapping. Biochem.
Biophys. Res. Commun. 304: 326-332, 2003.
4. Suzuki, T.; Park, H.; Hollingsworth, N. M.; Sternglanz, R.; Lennarz,
W. J.: PNG1, a yeast gene encoding a highly conserved peptide:N-glycanase. J.
Cell Biol. 149: 1039-1051, 2000.
5. Zhou, X.; Zhao, G.; Truglio, J. J.; Wang, L.; Li, G.; Lennarz,
W. J.; Schindelin, H.: Structural and biochemical studies of the
C-terminal domain of mouse peptide-N-glycanase identify it as a mannose-binding
module. Proc. Nat. Acad. Sci. 103: 17214-17219, 2006.
*FIELD* CN
Nara Sobreira - updated: 6/12/2013
*FIELD* CD
Patricia A. Hartz: 12/19/2006
*FIELD* ED
carol: 06/12/2013
carol: 6/12/2013
mgross: 12/19/2006
MIM
615273
*RECORD*
*FIELD* NO
615273
*FIELD* TI
#615273 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Iv; CDG1V
;;CDG Iv; CDGIv
*FIELD* TX
read moreA number sign (#) is used with this entry because of evidence that
congenital disorder of glycosylation type Iv (CDG1V) can be caused by
compound heterozygous mutation in the NGLY1 gene (610661) on chromosome
1p24. One such family has been described.
For a discussion of the classification of CDGs, see CDG1A (212065).
CLINICAL FEATURES
Need et al. (2012) and Shashi (2013) reported a boy with a phenotype
consistent with a congenital disorder of glycosylation. He presented
with developmental delay, hypotonia, involuntary movements, intractable
multifocal epilepsy, abnormal liver function, congenital absence of
tears, peripheral neuropathy, and small hands and feet. At age 15 months
he showed regression of motor development. At age 5 years he was able to
sit up, reach for objects, transfer them from hand to hand, but never
developed speech. Liver biopsy showed evidence of inflammatory changes
with an amorphous substance in the cytoplasm. Urine oligosaccharides
were abnormal, showing keratan sulfate, heparan sulfate, and chondroitin
sulfate. Brain MRI showed prominent perivascular spaces with surrounding
gliosis in periatrial white matter and mildly delayed myelination.
Testing for congenital disorders of glycosylation had been normal by
transferrin isoelectric focusing and N-glycan analysis.
MOLECULAR GENETICS
By whole-exome sequencing in a family in which a boy had developmental
delay, multifocal epilepsy, involuntary movements, abnormal liver
function, and absent tears, Need et al. (2012) found that the boy was
compound heterozygous for 2 mutations in the NGLY1 gene: a frameshift
mutation in exon 12 (610661.0001) inherited from his mother, and a
nonsense mutation in exon 8 (610661.0002) inherited from his father.
Need et al. (2012) compared NGLY1 protein expression in leukocytes
extracted from blood from the patient, his parents, and 3 controls. Both
parents showed reduced expression compared with controls, and the
patient had barely discernible levels of NGLY1.
*FIELD* RF
1. Need, A. C.; Shashi, V.; Hitomi, Y.; Schoch, K.; Shianna, K. V.;
McDonald, M. T.: Meisler, M. H.; Goldstein, D. B.: Clinical application
of exome sequencing in undiagnosed genetic conditions. J. Med. Genet. 49:
353-361, 2012.
2. Shashi, V.: Personal Communication. Durham, N.C. 6/11/2013.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Congenital absence of tears
ABDOMEN:
[Liver];
Abnormal liver function;
Inflammatory liver changes;
Amorphous substance in the cytoplasm
SKELETAL:
[Hands];
Small hands;
[Feet];
Small feet
NEUROLOGIC:
[Central nervous system];
Developmental delay;
Hypotonia;
Involuntary movements;
Epilepsy, multifocal, intractable;
Regression of motor development;
Prominent perivascular spaces with surrounding gliosis in periatrial
white matter;
Delayed myelination, mild;
[Peripheral nervous system];
Peripheral neuropathy
METABOLIC FEATURES:
Abnormal urine oligosaccharides (keratan sulfate, heparan sulfate,
and chondroitin sulfate);
Normal transferrin isoelectric focusing test;
Normal N-glycan analysis
MISCELLANEOUS:
MOLECULAR BASIS:
Caused by mutation in the N-glycanase 1 gene (NGLY1, 610661.0001)
*FIELD* CD
Nara Sobreira: 7/25/2013
*FIELD* ED
joanna: 07/25/2013
*FIELD* CN
Nara Sobreira - updated: 6/12/2013
*FIELD* CD
Nara Sobreira: 6/11/2013
*FIELD* ED
carol: 06/12/2013
carol: 6/12/2013
*RECORD*
*FIELD* NO
615273
*FIELD* TI
#615273 CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Iv; CDG1V
;;CDG Iv; CDGIv
*FIELD* TX
read moreA number sign (#) is used with this entry because of evidence that
congenital disorder of glycosylation type Iv (CDG1V) can be caused by
compound heterozygous mutation in the NGLY1 gene (610661) on chromosome
1p24. One such family has been described.
For a discussion of the classification of CDGs, see CDG1A (212065).
CLINICAL FEATURES
Need et al. (2012) and Shashi (2013) reported a boy with a phenotype
consistent with a congenital disorder of glycosylation. He presented
with developmental delay, hypotonia, involuntary movements, intractable
multifocal epilepsy, abnormal liver function, congenital absence of
tears, peripheral neuropathy, and small hands and feet. At age 15 months
he showed regression of motor development. At age 5 years he was able to
sit up, reach for objects, transfer them from hand to hand, but never
developed speech. Liver biopsy showed evidence of inflammatory changes
with an amorphous substance in the cytoplasm. Urine oligosaccharides
were abnormal, showing keratan sulfate, heparan sulfate, and chondroitin
sulfate. Brain MRI showed prominent perivascular spaces with surrounding
gliosis in periatrial white matter and mildly delayed myelination.
Testing for congenital disorders of glycosylation had been normal by
transferrin isoelectric focusing and N-glycan analysis.
MOLECULAR GENETICS
By whole-exome sequencing in a family in which a boy had developmental
delay, multifocal epilepsy, involuntary movements, abnormal liver
function, and absent tears, Need et al. (2012) found that the boy was
compound heterozygous for 2 mutations in the NGLY1 gene: a frameshift
mutation in exon 12 (610661.0001) inherited from his mother, and a
nonsense mutation in exon 8 (610661.0002) inherited from his father.
Need et al. (2012) compared NGLY1 protein expression in leukocytes
extracted from blood from the patient, his parents, and 3 controls. Both
parents showed reduced expression compared with controls, and the
patient had barely discernible levels of NGLY1.
*FIELD* RF
1. Need, A. C.; Shashi, V.; Hitomi, Y.; Schoch, K.; Shianna, K. V.;
McDonald, M. T.: Meisler, M. H.; Goldstein, D. B.: Clinical application
of exome sequencing in undiagnosed genetic conditions. J. Med. Genet. 49:
353-361, 2012.
2. Shashi, V.: Personal Communication. Durham, N.C. 6/11/2013.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Congenital absence of tears
ABDOMEN:
[Liver];
Abnormal liver function;
Inflammatory liver changes;
Amorphous substance in the cytoplasm
SKELETAL:
[Hands];
Small hands;
[Feet];
Small feet
NEUROLOGIC:
[Central nervous system];
Developmental delay;
Hypotonia;
Involuntary movements;
Epilepsy, multifocal, intractable;
Regression of motor development;
Prominent perivascular spaces with surrounding gliosis in periatrial
white matter;
Delayed myelination, mild;
[Peripheral nervous system];
Peripheral neuropathy
METABOLIC FEATURES:
Abnormal urine oligosaccharides (keratan sulfate, heparan sulfate,
and chondroitin sulfate);
Normal transferrin isoelectric focusing test;
Normal N-glycan analysis
MISCELLANEOUS:
MOLECULAR BASIS:
Caused by mutation in the N-glycanase 1 gene (NGLY1, 610661.0001)
*FIELD* CD
Nara Sobreira: 7/25/2013
*FIELD* ED
joanna: 07/25/2013
*FIELD* CN
Nara Sobreira - updated: 6/12/2013
*FIELD* CD
Nara Sobreira: 6/11/2013
*FIELD* ED
carol: 06/12/2013
carol: 6/12/2013