Structural Basis of Carbohydrate Transfer Activity by Human UDP-GalNAc: Polypeptide α-N-Acetylgalactosaminyltransferase (pp-GalNAc-T10)

Kubota, Tomomi; Shiba, T.; Sugioka, Shigemi; Furukawa, Shoei; Sawaki, Hiromichi; Kato, Ryuichi; Wakatsuki, Soichi; Narimatsu, Hisashi

doi:10.1016/j.jmb.2006.03.061

Cited by 113 publications

(103 citation statements)

References 51 publications

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“…Such domain mobility is supported by the superimposition of the x-ray crystal structures of ppGalNAc T1, T2, and T10, as shown in Fig. 6B (42,60,61). For those transferases with similar N-and C-terminal glycopeptide enhancements (Fig.…”

Section: Discussionmentioning

confidence: 65%

“…The ␤-subdomains of ppGalNAc T6 and T5 lack the QXW motif having EEW and LKW and would be expected to be inactive. Interestingly, the co-crystal structure of ppGalNAc T10 shows GalNAc-O-Ser bound to its ␤-subdomain (having canonical motifs CFD and QLW) (61). The ricin subdomain motifs of ppGalNAc T5 would be expected to have the weakest lectin binding activities because all three subdomains lack the critical Asp residue, although, in its ␥-subdomain, the Asp is replaced by a Glu.…”

Section: Discussionmentioning

confidence: 99%

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The Lectin Domain of the Polypeptide GalNAc Transferase Family of Glycosyltransferases (ppGalNAc Ts) Acts as a Switch Directing Glycopeptide Substrate Glycosylation in an N- or C-terminal Direction, Further Controlling Mucin Type O-Glycosylation

Gerken

Revoredo

Thome³

et al. 2013

Journal of Biological Chemistry

119

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Background: ppGalNAc transferases, which initiate O-glycosylation, possess a poorly understood lectin domain. Results:The lectin domain directs glycosylation in an N-or C-terminal direction in an isoform-specific manner. Conclusion: Unanticipated isoform-specific directionality was revealed for modification of glycopeptide substrates. Significance: A novel mechanism of controlling of mucin type O-glycosylation has been discovered based on tethered lectin domains specifying N-or C-terminal modification of glycopeptide substrates.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

The Lectin Domain of the Polypeptide GalNAc Transferase Family of Glycosyltransferases (ppGalNAc Ts) Acts as a Switch Directing Glycopeptide Substrate Glycosylation in an N- or C-terminal Direction, Further Controlling Mucin Type O-Glycosylation

Gerken

Revoredo

Thome³

et al. 2013

Journal of Biological Chemistry

119

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“…The domain organization of ppGalNAcTs is opposite that of POMGnT1; in these proteins, the C-terminal lectin domain is a β-trefoil fold also found in R-type lectins. The lectin domain binds GalNAc, a product of the catalytic domain of ppGalNAcTs, and modulates glycosylation of glycopeptide substrates (33,34). This mechanism resembles that of POMGnT1.…”

Section: Discussionmentioning

confidence: 99%

Carbohydrate-binding domain of the POMGnT1 stem region modulates O -mannosylation sites of α-dystroglycan

Kuwabara

Manya

Yamada

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The dystrophin glycoprotein complex, which connects the cell membrane to the basement membrane, is essential for a variety of biological events, including maintenance of muscle integrity. An O-mannose–type GalNAc-β1,3-GlcNAc-β1,4-(phosphate-6)-Man structure of α-dystroglycan (α-DG), a subunit of the complex that is anchored to the cell membrane, interacts directly with laminin in the basement membrane. Reduced glycosylation of α-DG is linked to some types of inherited muscular dystrophy; consistent with this relationship, many disease-related mutations have been detected in genes involved in O-mannosyl glycan synthesis. Defects in protein O-linked mannose β1,2-N-acetylglucosaminyltransferase 1 (POMGnT1), a glycosyltransferase that participates in the formation of GlcNAc-β1,2-Man glycan, are causally related to muscle-eye-brain disease (MEB), a congenital muscular dystrophy, although the role of POMGnT1 in postphosphoryl modification of GalNAc-β1,3-GlcNAc-β1,4-(phosphate-6)-Man glycan remains elusive. Our crystal structures of POMGnT1 agreed with our previous results showing that the catalytic domain recognizes substrate O-mannosylated proteins via hydrophobic interactions with little sequence specificity. Unexpectedly, we found that the stem domain recognizes the β-linked GlcNAc of O-mannosyl glycan, an enzymatic product of POMGnT1. This interaction may recruit POMGnT1 to a specific site of α-DG to promote GlcNAc-β1,2-Man clustering and also may recruit other enzymes that interact with POMGnT1, e.g., fukutin, which is required for further modification of the GalNAc-β1,3-GlcNAc-β1,4-(phosphate-6)-Man glycan. On the basis of our findings, we propose a mechanism for the deficiency in postphosphoryl modification of the glycan observed in POMGnT1-KO mice and MEB patients.

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“…These include the human Polypeptide a-N-Acetylgalactosaminyltransferase (ppGalNAc-T10; estimated precision 100%, E-value59.5e-12; see Fig. 5A) that transfers N-Acetylgalactosamine (Gal-NAc) from the substrate UDP-GalNAc to glycosylated peptides (Kubota et al, 2006), as well as the SpsA glycosyltransferase from Bacillus subtilis (estimated precision 100%, E-value51.4e-10; see supplementary material Fig. S3) that uses nucleotide-diphosphosugar donors to synthesise the bacterial spore coat (Charnock and Davies, 1999).…”

Section: Inn1 Regulates Chs2 During Cytokinesis 5457mentioning

confidence: 99%

Inn1 and Cyk3 regulate chitin synthase during cytokinesis in budding yeasts

Devrekanli

Foltman

Roncero

et al. 2012

Journal of Cell Science

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SummaryThe chitin synthase that makes the primary septum during cell division in budding yeasts is an important therapeutic target with an unknown activation mechanism. We previously found that the C2-domain of the Saccharomyces cerevisiae Inn1 protein plays an essential but uncharacterised role at the cleavage site during cytokinesis. By combining a novel degron allele of INN1 with a point mutation in the C2-domain, we screened for mutations in other genes that suppress the resulting defect in cell division. In this way, we identified 22 dominant mutations of CHS2 (chitin synthase II) that map to two neighbouring sites in the catalytic domain. Chs2 in isolated cell membranes is normally nearly inactive (unless protease treatment is used to bypass inhibition); however, the dominant suppressor allele Chs2-V377I has enhanced activity in vitro. We show that Inn1 associates with Chs2 in yeast cell extracts. It also interacts in a yeast two-hybrid assay with the N-terminal 65% of Chs2, which contains the catalytic domain. In addition to compensating for mutations in the Inn1 C2-domain, the dominant CHS2 alleles suppress cytokinesis defects produced by the lack of the Cyk3 protein.Our data support a model in which the C2-domain of Inn1 acts in conjunction with Cyk3 to regulate the catalytic domain of Chs2 during cytokinesis. These findings suggest novel approaches for developing future drugs against important fungal pathogens.

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Structural Basis of Carbohydrate Transfer Activity by Human UDP-GalNAc: Polypeptide α-N-Acetylgalactosaminyltransferase (pp-GalNAc-T10)

Cited by 113 publications

References 51 publications

The Lectin Domain of the Polypeptide GalNAc Transferase Family of Glycosyltransferases (ppGalNAc Ts) Acts as a Switch Directing Glycopeptide Substrate Glycosylation in an N- or C-terminal Direction, Further Controlling Mucin Type O-Glycosylation

The Lectin Domain of the Polypeptide GalNAc Transferase Family of Glycosyltransferases (ppGalNAc Ts) Acts as a Switch Directing Glycopeptide Substrate Glycosylation in an N- or C-terminal Direction, Further Controlling Mucin Type O-Glycosylation

Carbohydrate-binding domain of the POMGnT1 stem region modulates O -mannosylation sites of α-dystroglycan

Inn1 and Cyk3 regulate chitin synthase during cytokinesis in budding yeasts

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