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NGLY1

This article was updated by an external expert under a dual publication model. The corresponding peer-reviewed article was published in the journal Gene. Click to view.
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NGLY1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesNGLY1, CDG1V, PNG1, PNGase, CDDG, N-glycanase 1, PNG-1
External IDsOMIM: 610661; MGI: 1913276; HomoloGene: 10117; GeneCards: NGLY1; OMA:NGLY1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

55768

59007

Ensembl

ENSG00000151092

ENSMUSG00000021785

UniProt

Q96IV0

Q9JI78

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: 6.16 – 6.22 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 60 patients have been reported in the literature and over 100 have been identified by patient advocacy groups.[41][42][43][44] One cerebral visual impairment (CVI) patient also had a mutation in NGLY1 gene.[45] 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 remain unknown, while the intracellular accumulation of N-GlcNAc proteins, due to the excess action of cytosolic endo-b-N-acetylglucosaminidase[46] to misfolded glycoproteins, in Ngly1-deficient cells has been hypothesized as a potential cause.[28]

NGLY1 deficiency has drawn attention in the public.[47][48][49][50]

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 in the treatment of disorder caused by NGLY1 defects.[51]

Notes

[edit]

References

[edit]
  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000151092 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021785 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Hirayama H, Hosomi A, Suzuki T (May 2015). "Physiological and molecular functions of the cytosolic peptide:N-glycanase". Seminars in Cell & Developmental Biology. 41: 110–120. doi:10.1016/j.semcdb.2014.11.009. PMID 25475175.
  6. ^ Suzuki T (January 2015). "The cytoplasmic peptide:N-glycanase (Ngly1)-basic science encounters a human genetic disorder". Journal of Biochemistry. 157 (1): 23–34. doi:10.1093/jb/mvu068. PMID 25398991.
  7. ^ Suzuki T, Huang C, Fujihira H (February 2016). "The cytoplasmic peptide:N-glycanase (NGLY1) - Structure, expression and cellular functions". Gene. 577 (1): 1–7. doi:10.1016/j.gene.2015.11.021. PMC 4691572. PMID 26611529.
  8. ^ a b Suzuki T, Seko A, Kitajima K, Inoue Y, Inoue S (August 1993). "Identification of peptide:N-glycanase activity in mammalian-derived cultured cells". Biochemical and Biophysical Research Communications. 194 (3): 1124–1130. doi:10.1006/bbrc.1993.1938. PMID 8352768.
  9. ^ Takahashi N (June 1977). "Demonstration of a new amidase acting on glycopeptides". Biochemical and Biophysical Research Communications. 76 (4): 1194–1201. doi:10.1016/0006-291x(77)90982-2. PMID 901470.
  10. ^ Plummer TH, Elder JH, Alexander S, Phelan AW, Tarentino AL (September 1984). "Demonstration of peptide:N-glycosidase F activity in endo-beta-N-acetylglucosaminidase F preparations". The Journal of Biological Chemistry. 259 (17): 10700–10704. doi:10.1016/S0021-9258(18)90568-5. PMID 6206060.
  11. ^ Suzuki T, Seko A, Kitajima K, Inoue Y, Inoue S (July 1994). "Purification and enzymatic properties of peptide:N-glycanase from C3H mouse-derived L-929 fibroblast cells. Possible widespread occurrence of post-translational remodification of proteins by N-deglycosylation". The Journal of Biological Chemistry. 269 (26): 17611–17618. doi:10.1016/S0021-9258(17)32485-7. PMID 8021270.
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  17. ^ a b Suzuki T, Park H, Till EA, Lennarz WJ (October 2001). "The PUB domain: a putative protein-protein interaction domain implicated in the ubiquitin-proteasome pathway". Biochemical and Biophysical Research Communications. 287 (5): 1083–1087. doi:10.1006/bbrc.2001.5688. PMID 11587532.
  18. ^ a b Doerks T, Copley RR, Schultz J, Ponting CP, Bork P (January 2002). "Systematic identification of novel protein domain families associated with nuclear functions". Genome Research. 12 (1): 47–56. doi:10.1101/gr.203201. PMC 155265. PMID 11779830.
  19. ^ Allen MD, Buchberger A, Bycroft M (September 2006). "The PUB domain functions as a p97 binding module in human peptide N-glycanase". The Journal of Biological Chemistry. 281 (35): 25502–25508. doi:10.1074/jbc.M601173200. PMID 16807242.
  20. ^ a b Kamiya Y, Uekusa Y, Sumiyoshi A, Sasakawa H, Hirao T, Suzuki T, Kato K (April 2012). "NMR characterization of the interaction between the PUB domain of peptide:N-glycanase and ubiquitin-like domain of HR23". FEBS Letters. 586 (8): 1141–1146. doi:10.1016/j.febslet.2012.03.027. PMID 22575648. S2CID 23573555.
  21. ^ Schaeffer V, Akutsu M, Olma MH, Gomes LC, Kawasaki M, Dikic I (May 2014). "Binding of OTULIN to the PUB domain of HOIP controls NF-κB signaling". Molecular Cell. 54 (3): 349–361. doi:10.1016/j.molcel.2014.03.016. PMID 24726327.
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  26. ^ Hirsch C, Blom D, Ploegh HL (March 2003). "A role for N-glycanase in the cytosolic turnover of glycoproteins". The EMBO Journal. 22 (5): 1036–1046. doi:10.1093/emboj/cdg107. PMC 150340. PMID 12606569.
  27. ^ Grotzke JE, Lu Q, Cresswell P (February 2013). "Deglycosylation-dependent fluorescent proteins provide unique tools for the study of ER-associated degradation". Proceedings of the National Academy of Sciences of the United States of America. 110 (9): 3393–3398. Bibcode:2013PNAS..110.3393G. doi:10.1073/pnas.1300328110. PMC 3587246. PMID 23401531.
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  32. ^ Dalet A, Robbins PF, Stroobant V, Vigneron N, Li YF, El-Gamil M, et al. (July 2011). "An antigenic peptide produced by reverse splicing and double asparagine deamidation". Proceedings of the National Academy of Sciences of the United States of America. 108 (29): E323–E331. Bibcode:2011PNAS..108E.323D. doi:10.1073/pnas.1101892108. PMC 3142003. PMID 21670269.
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  35. ^ Katiyar S, Li G, Lennarz WJ (September 2004). "A complex between peptide:N-glycanase and two proteasome-linked proteins suggests a mechanism for the degradation of misfolded glycoproteins". Proceedings of the National Academy of Sciences of the United States of America. 101 (38): 13774–13779. Bibcode:2004PNAS..10113774K. doi:10.1073/pnas.0405663101. PMC 518832. PMID 15358861.
  36. ^ Katiyar S, Joshi S, Lennarz WJ (October 2005). "The retrotranslocation protein Derlin-1 binds peptide:N-glycanase to the endoplasmic reticulum". Molecular Biology of the Cell. 16 (10): 4584–4594. doi:10.1091/mbc.E05-04-0345. PMC 1237066. PMID 16055502.
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  41. ^ Levy RJ, Frater CH, Gallentine WB, Phillips JM, Ruzhnikov MR (March 2022). "Delineating the epilepsy phenotype of NGLY1 deficiency". Journal of Inherited Metabolic Disease. 45 (3): 571–583. doi:10.1002/jimd.12494. PMID 35243670. S2CID 247228775.
  42. ^ Enns GM, Shashi V, Bainbridge M, Gambello MJ, Zahir FR, Bast T, et al. (October 2014). "Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway". Genetics in Medicine. 16 (10): 751–758. doi:10.1038/gim.2014.22. PMC 4243708. PMID 24651605.
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  51. ^ Srinivasan B, Zhou H, Mitra S, Skolnick J (October 2016). "Novel small molecule binders of human N-glycanase 1, a key player in the endoplasmic reticulum associated degradation pathway". Bioorganic & Medicinal Chemistry. 24 (19): 4750–4758. doi:10.1016/j.bmc.2016.08.019. PMC 5015769. PMID 27567076.

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