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Human N-acetylglucosaminyltransferase II substrate recognition uses a modular architecture that includes a convergent exosite.

Kadirvelraj R, Yang JY, Sanders JH, Liu L, Ramiah A, Prabhakar PK, Boons GJ, Wood ZA, Moremen KW
Proc Natl Acad Sci U S A 115 4637-4642 (2018)
Related entries: 5vcr, 5vcs

Cited: 24 times
EuropePMC logo PMID: 29666272

Abstract

Asn-linked oligosaccharides are extensively modified during transit through the secretory pathway, first by trimming of the nascent glycan chains and subsequently by initiating and extending multiple oligosaccharide branches from the trimannosyl glycan core. Trimming and branching pathway steps are highly ordered and hierarchal based on the precise substrate specificities of the individual biosynthetic enzymes. A key committed step in the synthesis of complex-type glycans is catalyzed by N-acetylglucosaminyltransferase II (MGAT2), an enzyme that generates the second GlcNAcβ1,2- branch from the trimannosyl glycan core using UDP-GlcNAc as the sugar donor. We determined the structure of human MGAT2 as a Mn2+-UDP donor analog complex and as a GlcNAcMan3GlcNAc2-Asn acceptor complex to reveal the structural basis for substrate recognition and catalysis. The enzyme exhibits a GT-A Rossmann-like fold that employs conserved divalent cation-dependent substrate interactions with the UDP-GlcNAc donor. MGAT2 interactions with the extended glycan acceptor are distinct from other related glycosyltransferases. These interactions are composed of a catalytic subsite that binds the Man-α1,6- monosaccharide acceptor and a distal exosite pocket that binds the GlcNAc-β1,2Man-α1,3Manβ- substrate "recognition arm." Recognition arm interactions are similar to the enzyme-substrate interactions for Golgi α-mannosidase II, a glycoside hydrolase that acts just before MGAT2 in the Asn-linked glycan biosynthetic pathway. These data suggest that substrate binding by MGAT2 employs both conserved and convergent catalytic subsite modules to provide substrate selectivity and catalysis. More broadly, the MGAT2 active-site architecture demonstrates how glycosyltransferases create complementary modular templates for regiospecific extension of glycan structures in mammalian cells.

Reviews - 5vcm mentioned but not cited (2)

  1. Emerging structural insights into glycosyltransferase-mediated synthesis of glycans. Moremen KW, Haltiwanger RS. Nat Chem Biol 15 853-864 (2019)
  2. 3D Structure and Function of Glycosyltransferases Involved in N-glycan Maturation. Nagae M, Yamaguchi Y, Taniguchi N, Kizuka Y. Int J Mol Sci 21 E437 (2020)

Articles - 5vcm mentioned but not cited (3)

  1. Human N-acetylglucosaminyltransferase II substrate recognition uses a modular architecture that includes a convergent exosite. Kadirvelraj R, Yang JY, Sanders JH, Liu L, Ramiah A, Prabhakar PK, Boons GJ, Wood ZA, Moremen KW. Proc Natl Acad Sci U S A 115 4637-4642 (2018)
  2. A photo-cross-linking GlcNAc analog enables covalent capture of N-linked glycoprotein-binding partners on the cell surface. Wu H, Shajahan A, Yang JY, Capota E, Wands AM, Arthur CM, Stowell SR, Moremen KW, Azadi P, Kohler JJ. Cell Chem Biol 29 84-97.e8 (2022)
  3. Structure-based design of UDP-GlcNAc analogs as candidate GnT-V inhibitors. Vibhute AM, Tanaka HN, Mishra SK, Osuka RF, Nagae M, Yonekawa C, Korekane H, Doerksen RJ, Ando H, Kizuka Y. Biochim Biophys Acta Gen Subj 1866 130118 (2022)


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  1. Recent progress in synthesis of carbohydrates with sugar nucleotide-dependent glycosyltransferases. Na L, Li R, Chen X. Curr Opin Chem Biol 61 81-95 (2021)
  2. Promiscuity and specificity of eukaryotic glycosyltransferases. Biswas A, Thattai M. Biochem Soc Trans 48 891-900 (2020)
  3. Critical Determinants in ER-Golgi Trafficking of Enzymes Involved in Glycosylation. Zhang N, Zabotina OA. Plants (Basel) 11 428 (2022)
  4. N-linked glycans: an underappreciated key determinant of T cell development, activation, and function. Abdelbary M, Nolz JC. Immunometabolism (Cobham) 5 e00035 (2023)

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  1. Structure and mechanism of cancer-associated N-acetylglucosaminyltransferase-V. Nagae M, Kizuka Y, Mihara E, Kitago Y, Hanashima S, Ito Y, Takagi J, Taniguchi N, Yamaguchi Y. Nat Commun 9 3380 (2018)
  2. Deep evolutionary analysis reveals the design principles of fold A glycosyltransferases. Taujale R, Venkat A, Huang LC, Zhou Z, Yeung W, Rasheed KM, Li S, Edison AS, Moremen KW, Kannan N. Elife 9 e54532 (2020)
  3. Structural basis for substrate specificity and catalysis of α1,6-fucosyltransferase. García-García A, Ceballos-Laita L, Serna S, Artschwager R, Reichardt NC, Corzana F, Hurtado-Guerrero R. Nat Commun 11 973 (2020)
  4. Characterizing human α-1,6-fucosyltransferase (FUT8) substrate specificity and structural similarities with related fucosyltransferases. Boruah BM, Kadirvelraj R, Liu L, Ramiah A, Li C, Zong G, Bosman GP, Yang JY, Wang LX, Boons GJ, Wood ZA, Moremen KW. J Biol Chem 295 17027-17045 (2020)
  5. Comparison of human poly-N-acetyl-lactosamine synthase structure with GT-A fold glycosyltransferases supports a modular assembly of catalytic subsites. Kadirvelraj R, Yang JY, Kim HW, Sanders JH, Moremen KW, Wood ZA. J Biol Chem 296 100110 (2021)
  6. Modulation of hepatocyte sialylation drives spontaneous fatty liver disease and inflammation. Oswald DM, Jones MB, Cobb BA. Glycobiology 30 346-359 (2020)
  7. A universal glycoenzyme biosynthesis pipeline that enables efficient cell-free remodeling of glycans. Jaroentomeechai T, Kwon YH, Liu Y, Young O, Bhawal R, Wilson JD, Li M, Chapla DG, Moremen KW, Jewett MC, Mizrachi D, DeLisa MP. Nat Commun 13 6325 (2022)
  8. Glycoprotein In Vitro N-Glycan Processing Using Enzymes Expressed in E. coli. Zhang L, Li Y, Li R, Yang X, Zheng Z, Fu J, Yu H, Chen X. Molecules 28 2753 (2023)
  9. Increased levels of acidic free-N-glycans, including multi-antennary and fucosylated structures, in the urine of cancer patients. Hanzawa K, Tanaka-Okamoto M, Murakami H, Suzuki N, Mukai M, Takahashi H, Omori T, Ikezawa K, Ohkawa K, Ohue M, Natsuka S, Miyamoto Y. PLoS One 17 e0266927 (2022)
  10. Production of galactosylated complex-type N-glycans in glycoengineered Saccharomyces cerevisiae. Piirainen MA, Salminen H, Frey AD. Appl Microbiol Biotechnol 106 301-315 (2022)
  11. Discovery of a lectin domain that regulates enzyme activity in mouse N-acetylglucosaminyltransferase-IVa (MGAT4A). Nagae M, Hirata T, Tateno H, Mishra SK, Manabe N, Osada N, Tokoro Y, Yamaguchi Y, Doerksen RJ, Shimizu T, Kizuka Y. Commun Biol 5 695 (2022)
  12. Limited N-Glycan Processing Impacts Chaperone Expression Patterns, Cell Growth and Cell Invasiveness in Neuroblastoma. Hall MK, Shajahan A, Burch AP, Hatchett CJ, Azadi P, Schwalbe RA. Biology (Basel) 12 293 (2023)
  13. Asymmetrical Biantennary Glycans Prepared by a Stop-and-Go Strategy Reveal Receptor Binding Evolution of Human Influenza A Viruses. Ma S, Liu L, Eggink D, Herfst S, Fouchier RAM, de Vries RP, Boons GJ. JACS Au 4 607-618 (2024)
  14. Glycosyltransferase 8 domain-containing protein 1 (GLT8D1) is a UDP-dependent galactosyltransferase. Vicente JB, Guerreiro ACL, Felgueiras B, Chapla D, Tehrani D, Moremen KW, Costa J. Sci Rep 13 21684 (2023)
  15. Lectin inspired polymers based on the dipeptide Ser-Asp for glycopeptide enrichment. Zhang B, Yu RZ, Yu YH, Peng C, Xie R, Zhang Y, Chen JY. Analyst 143 5090-5093 (2018)


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