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NGLY1

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NGLY1
Protein NGLY1 PDB 2ccq.png
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesNGLY1, CDG1V, PNG1, PNGase, CDDG, N-glycanase 1
External IDsMGI: 1913276 HomoloGene: 10117 GeneCards: NGLY1
Gene location (Human)
Chromosome 3 (human)
Chr.Chromosome 3 (human)[1]
Chromosome 3 (human)
Genomic location for NGLY1
Genomic location for NGLY1
Band3p24.2Start25,718,944 bp[1]
End25,790,039 bp[1]
RNA expression pattern
PBB GE NGLY1 220742 s at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001145293
NM_001145294
NM_001145295
NM_018297
NM_025105

NM_021504
NM_001362432
NM_001362433

RefSeq (protein)

NP_001138765
NP_001138766
NP_001138767
NP_060767

NP_067479
NP_001349361
NP_001349362

Location (UCSC)Chr 3: 25.72 – 25.79 MbChr 14: 16.25 – 16.31 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

PNGase also known as N-glycanase 1 (EC 3.5.1.52) or peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase is an enzyme that in humans is encoded by the NGLY1 gene. PNGase is a de-N-glycosylating enzyme that removes N-linked or asparagine-linked glycans (N-glycans) from glycoproteins.[5][6][7] More specifically, NGLY1 catalyzes the hydrolysis of the amide bond between the innermost N-acetylglucosamine (GlcNAc) and an Asn residue on an N-glycoprotein, generating a de-N-glycosylated protein, in which the N-glycoylated Asn residue is converted to asp, and a 1-amino-GlcNAc-containing free oligosaccharide. Ammonia is then spontaneously released from the 1-amino GlcNAc at physiological pH (<8), giving rise to a free oligosaccharide with an N,N’-diacetylchitobiose structure at the reducing end.

Discovery[edit]

Occurrence of cytoplasmic PNGase activity in mammalian cells was first reported in cultured cells.[8] This enzyme differ from other “reagent” PNGases from almond (glycoamidase/PNGase A),[9] or bacteria (N-glycanase/PNGase F),[10] that is often used for structural/functional studies of N-glycans, in several enzymatic properties, including the requirement of a reducing reagent for activity and a neutral pH for optimal activity.[8][11][12]

The gene encoding the cytoplasmic PNGase was first identified in budding yeast, Saccharomyces cerevisiae and gene orthologues have since been found in wide variety of eukaryotes including mammals.[13] In terms of the tissue distribution of the mouse Ngly1 gene, enzyme activities as well as transcripts were detected in all tissues/organs examined.[12][14]

Structure[edit]

The catalytic residues of the cytoplasmic PNGase is known to reside in a domain called transglutaminase domain.[15][16] NGLY1, when compared with the yeast orthologues, possesses extended N-terminal and C-terminal sequences in addition to the transglutaminase domain. Among the additional domains found in NGLY1, the PUB (PNGase- and ubiquitin-related) domain was first identified through a bioinformatics analysis.[17][18] While it was initially hypothesized that it might serve as a protein-protein interaction domain,[17] experimental evidence supporting this hypothesis is now accumulating.[19][20][21] On the other hand, the C-terminal PAW domain (a domain present in PNGases and other worm proteins).[18] has now been shown to be involved in the binding of oligosaccharides to PNGase.[22]

In terms of the crystal structures of mouse Ngly1, a catalytic core domain,[23] a C-terminal domain including PAW domain[22] and an N-terminal domain including PUB domain.[24] have been obtained.

Function[edit]

Regarding the function of NGLY1, it has been shown that the enzyme is involved in the ER-associated degradation (ERAD), one of the ER quality control/homeostasis systems for newly synthesized glycoproteins.[25][26][27][28] The functional importance of NGLY1 in the ERAD process, however, is not clearly understood. It has also been suggested that NGLY1 is closely involved in MHC class I-mediated antigen presentation.[29][30][31] The Ngly1-mediated (glycosylated) Asn-to-Asp deamidation constitutes, together with other reactions such as transpeptidation, unconventional post-translational modifications for antigenic peptides that are presented by MHC class I molecules.[32]

NGLY1-binding proteins[edit]

Through yeast two-hybrid screening, it has been shown that NGLY1 proteins can bind to several proteins, mostly through the N-terminal domain including the PUB domain.[33] In vivo and in vitro interactions between NGLY1 and several ERAD-related proteins have been reported.[20][23][24][33][34][35][36][37][38] While the importance of those protein-protein interactions to NGLY1 functions remain to be clarified, it can be assumed that such interactions may be advantageous for an efficient ERAD process.[39]

Clinical significance[edit]

In 2012, NGLY1 deficiency, involving mutations in the NGLY1 gene locus was first identified through an exome analysis.[40] As of now, the clinical features of 11 patients have been reported.[41][42][43] One cerebral visual impairment (CVI) patient also had a mutation in NGLY1 gene.[44]The clinical effects include neuromotor impairment, intellectual disability, and neuropathy. It has also been associated with amyotrophic lateral sclerosis and Parkinson's disease.

Details of the mechanism responsible for the pathogenesis of the NGLY1-deficiency remains unknown, while the intracellular accumulation of N-GlcNAc proteins, due to the excess action of cytosolic endo-b-N-acetylglucosaminidase[45] to misfolded glycoproteins, in Ngly1-deficient cells has been hypothesized as a potential cause.[28]

NGLY1 deficiency has drawn attention in the public.[46][47][48][49]

Studies have been carried out to discover small-molecules that can bind to the transglutaminase domain of the protein to stabilize it as a potential therapeutic applications in the treatment of disorder caused by NGLY1 mutants.[50]

Notes[edit]


References[edit]

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  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021785 - Ensembl, May 2017
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.