Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase (NGLY1)

The protein contains 654 amino acids for an estimated molecular weight of 74390 Da.

 

Specifically deglycosylates the denatured form of N-linked glycoproteins in the cytoplasm and assists their proteasome-mediated degradation. Cleaves the beta-aspartyl-glucosamine (GlcNAc) of the glycan and the amide side chain of Asn, converting Asn to Asp. Prefers proteins containing high-mannose over those bearing complex type oligosaccharides. Can recognize misfolded proteins in the endoplasmic reticulum that are exported to the cytosol to be destroyed and deglycosylate them, while it has no activity toward native proteins. Deglycosylation is a prerequisite for subsequent proteasome-mediated degradation of some, but not all, misfolded glycoproteins. (updated: March 4, 2015)

Protein identification was indicated in the following studies:

  1. Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
  2. Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
  3. D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

PublicationIdentification 1Uniprot mapping 2Not mapped /
Obsolete
TrEMBLSwiss-Prot
Goodman (2013)2289 (gene list)227853205992269
Lange (2014)123412347281224
Hegedus (2015)2638262202352387
Wilson (2016)165815281702911068
d'Alessandro (2017)18261817201815
Bryk (2017)20902060101081942
Chu (2018)18531804553621387

1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.

Interpro domains
Total structural coverage: 61%
Model score: 29

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VariantDescription
dbSNP:rs7621398
dbSNP:rs7635089

The reference OMIM entry for this protein is 610661

N-glycanase 1; ngly1
Peptide-n-glycanase 1, s. cerevisiae, homolog of; png1

DESCRIPTION

The NGLY1 gene encodes N-glycanase (EC 3.5.1.52), 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). NGLY1 is a cytoplasmic component of the endoplasmic reticulum-associated degradation (ERAD) pathway that identifies and degrades misfolded glycoproteins (summary by Enns et al., 2014).

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 deglycosylation (CDDG; 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 (R401X; 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. In 5 patients from 3 families with CDDG, Enns et al. (2014) identified a homozygous R401X mutation in the NGLY1 gene. All of the patients were Caucasian and of European descent, suggesting the possibility of a founder mutation. Two additional patients were found to carry biallelic NGLY1 mutations (610661.0003-610661.0005). The patients had global developmental delay, hypotonia, and a movement disorder. Other features included hypolacrima or alacrima, abnormal liver enzymes, microcephaly, and seizures. Liver biopsy showed cytoplasmic accumulation of storage material in vacuoles, consistent with accumu ... More on the omim web site

Subscribe to this protein entry history

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 610661 was added.

Feb. 24, 2016: Protein entry updated
Automatic update: model status changed