NGLY1

Last updated
NGLY1
Protein NGLY1 PDB 2ccq.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases NGLY1 , CDG1V, PNG1, PNGase, CDDG, N-glycanase 1, PNG-1
External IDs OMIM: 610661 MGI: 1913276 HomoloGene: 10117 GeneCards: NGLY1
Orthologs
SpeciesHumanMouse
Entrez

55768

59007

Ensembl

ENSG00000151092

ENSMUSG00000021785

UniProt

Q96IV0

Q9JI78

RefSeq (mRNA)

NM_001145293
NM_001145294
NM_001145295
NM_018297
NM_025105

Contents

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 Mb Chr 14: 6.16 – 6.22 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/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

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

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

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

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

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

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William Joseph Lennarz was a biochemist at Stony Brook University. He was born in May 1934 in New York City. Before Lennarz began his tenure at Stony Brook, he studied chemistry and organic chemistry. After working as a postdoctoral researcher at Harvard, he developed an interest in biochemistry. He has focused the majority of his research on biochemical processes in cells.

References

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  2. 1 2 3 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.
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  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.
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  15. ↑ Makarova KS, Aravind L, Koonin EV (August 1999). "A superfamily of archaeal, bacterial, and eukaryotic proteins homologous to animal transglutaminases". Protein Science. 8 (8): 1714–1719. doi:10.1110/ps.8.8.1714. PMC   2144420 . PMID   10452618.
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  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. 1 2 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.
  22. 1 2 Zhou X, Zhao G, Truglio JJ, Wang L, Li G, Lennarz WJ, Schindelin H (November 2006). "Structural and biochemical studies of the C-terminal domain of mouse peptide-N-glycanase identify it as a mannose-binding module". Proceedings of the National Academy of Sciences of the United States of America. 103 (46): 17214–17219. Bibcode:2006PNAS..10317214Z. doi: 10.1073/pnas.0602954103 . PMC   1859912 . PMID   17088551.
  23. 1 2 Zhao G, Zhou X, Wang L, Li G, Kisker C, Lennarz WJ, Schindelin H (May 2006). "Structure of the mouse peptide N-glycanase-HR23 complex suggests co-evolution of the endoplasmic reticulum-associated degradation and DNA repair pathways". The Journal of Biological Chemistry. 281 (19): 13751–13761. doi: 10.1074/jbc.M600137200 . PMID   16500903.
  24. 1 2 Zhao G, Zhou X, Wang L, Li G, Schindelin H, Lennarz WJ (May 2007). "Studies on peptide:N-glycanase-p97 interaction suggest that p97 phosphorylation modulates endoplasmic reticulum-associated degradation". Proceedings of the National Academy of Sciences of the United States of America. 104 (21): 8785–8790. Bibcode:2007PNAS..104.8785Z. doi: 10.1073/pnas.0702966104 . PMC   1885580 . PMID   17496150.
  25. ↑ Wiertz EJ, Jones TR, Sun L, Bogyo M, Geuze HJ, Ploegh HL (March 1996). "The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol". Cell. 84 (5): 769–779. doi: 10.1016/s0092-8674(00)81054-5 . PMID   8625414. S2CID   5122267.
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  34. ↑ McNeill H, Knebel A, Arthur JS, Cuenda A, Cohen P (December 2004). "A novel UBA and UBX domain protein that binds polyubiquitin and VCP and is a substrate for SAPKs". The Biochemical Journal. 384 (Pt 2): 391–400. doi:10.1042/BJ20041498. PMC   1134123 . PMID   15362974.
  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.
  37. ↑ Li G, Zhou X, Zhao G, Schindelin H, Lennarz WJ (November 2005). "Multiple modes of interaction of the deglycosylation enzyme, mouse peptide N-glycanase, with the proteasome". Proceedings of the National Academy of Sciences of the United States of America. 102 (44): 15809–15814. Bibcode:2005PNAS..10215809L. doi: 10.1073/pnas.0507155102 . PMC   1276080 . PMID   16249333.
  38. ↑ Li G, Zhao G, Zhou X, Schindelin H, Lennarz WJ (May 2006). "The AAA ATPase p97 links peptide N-glycanase to the endoplasmic reticulum-associated E3 ligase autocrine motility factor receptor". Proceedings of the National Academy of Sciences of the United States of America. 103 (22): 8348–8353. Bibcode:2006PNAS..103.8348L. doi: 10.1073/pnas.0602747103 . PMC   1482497 . PMID   16709668.
  39. ↑ Suzuki T, Lennarz WJ (February 2003). "Hypothesis: a glycoprotein-degradation complex formed by protein-protein interaction involves cytoplasmic peptide:N-glycanase". Biochemical and Biophysical Research Communications. 302 (1): 1–5. doi:10.1016/s0006-291x(03)00052-4. PMID   12593838.
  40. ↑ Need AC, Shashi V, Hitomi Y, Schoch K, Shianna KV, McDonald MT, et al. (June 2012). "Clinical application of exome sequencing in undiagnosed genetic conditions". Journal of Medical Genetics. 49 (6): 353–361. doi:10.1136/jmedgenet-2012-100819. PMC   3375064 . PMID   22581936.
  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.
  43. ↑ Caglayan AO, Comu S, Baranoski JF, Parman Y, Kaymakçalan H, Akgumus GT, et al. (January 2015). "NGLY1 mutation causes neuromotor impairment, intellectual disability, and neuropathy". European Journal of Medical Genetics. 58 (1): 39–43. doi:10.1016/j.ejmg.2014.08.008. PMC   4804755 . PMID   25220016.
  44. ↑ Heeley J, Shinawi M (April 2015). "Multi-systemic involvement in NGLY1-related disorder caused by two novel mutations". American Journal of Medical Genetics. Part A. 167A (4): 816–820. doi:10.1002/ajmg.a.36889. PMID   25707956. S2CID   7959186.
  45. ↑ Bosch DG, Boonstra FN, de Leeuw N, Pfundt R, Nillesen WM, de Ligt J, et al. (May 2016). "Novel genetic causes for cerebral visual impairment". European Journal of Human Genetics. 24 (5): 660–665. doi:10.1038/ejhg.2015.186. PMC   4930090 . PMID   26350515.
  46. ↑ Suzuki T, Yano K, Sugimoto S, Kitajima K, Lennarz WJ, Inoue S, et al. (July 2002). "Endo-beta-N-acetylglucosaminidase, an enzyme involved in processing of free oligosaccharides in the cytosol". Proceedings of the National Academy of Sciences of the United States of America. 99 (15): 9691–9696. Bibcode:2002PNAS...99.9691S. doi: 10.1073/pnas.152333599 . PMC   124980 . PMID   12114544.
  47. ↑ "Kids who don't cry: New genetic disorder discovered". 20 March 2014.
  48. ↑ Mnookin S (14 July 2014). "One of a Kind". The New Yorker .
  49. ↑ "Hunting down my son's killer".
  50. ↑ Might M, Wilsey M (October 2014). "The shifting model in clinical diagnostics: how next-generation sequencing and families are altering the way rare diseases are discovered, studied, and treated". Genetics in Medicine. 16 (10): 736–737. doi: 10.1038/gim.2014.23 . PMID   24651604. S2CID   27270375.
  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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