Homology between O-linked GlcNAc transferases and proteins of the glycogen phosphorylase superfamily

James O. Wrabl, Nick V. Grishin

Research output: Contribution to journalArticle

104 Citations (Scopus)

Abstract

The O-linked GlcNAc transferases (OGTs) are a recently characterized group of largely eukaryotic enzymes that add a single β-N-acetylglucosamine moiety to specific serine or threonine hydroxyls. In humans, this process may be part of a sugar regulation mechanism or cellular signaling pathway that is involved in many important diseases, such as diabetes, cancer, and neurodegeneration. However, no structural information about the human OGT exists, except for the identification of tetratricopeptide repeats (TPR) at the N terminus. The locations of substrate binding sites are unknown and the structural basis for this enzyme's function is not clear. Here, remote homology is reported between the OGTs and a large group of diverse sugar processing enzymes, including proteins with known structure such as glycogen phosphorylase, UDP-GlcNAc 2-epimerase, and the glycosyl transferase MurG. This relationship, in conjunction with amino acid similarity spanning the entire length of the sequence, implies that the fold of the human OGT consists of two Rossmann-like domains C-terminal to the TPR region. A conserved motif in the second Rossmann domain points to the UDP-GlcNAc donor binding site. This conclusion is supported by a combination of statistically significant PSI-BLAST hits, consensus secondary structure predictions, and a fold recognition hit to MurG. Additionally, iterative PSI-BLAST database searches reveal that proteins homologous to the OGTs form a large and diverse superfamily that is termed GPGTF (glycogen phosphorylase/glycosyl transferase). Up to one-third of the 51 functional families in the CAZY database, a glycosyl transferase classification scheme based on catalytic residue and sequence homology considerations, can be unified through this common predicted fold. GPGTF homologs constitute a substantial fraction of known proteins: 0.4% of all non-redundant sequences and about 1 % of proteins in the Escherichia coli genome are found to belong to the GPGTF superfamily.

Original languageEnglish (US)
Pages (from-to)365-374
Number of pages10
JournalJournal of Molecular Biology
Volume314
Issue number3
DOIs
StatePublished - Nov 30 2001

Fingerprint

Glycogen Phosphorylase
Transferases
Proteins
Enzymes
Binding Sites
Databases
Uridine Diphosphate
Acetylglucosamine
Escherichia coli Proteins
Threonine
Sequence Homology
Hydroxyl Radical
Serine
O-GlcNAc transferase
Genome
Amino Acids
Neoplasms

Keywords

  • Fold prediction
  • Glycogen phosphorylase
  • Glycosyl transferase
  • Homology detection
  • O-linked GlcNAc transferase

ASJC Scopus subject areas

  • Virology

Cite this

Homology between O-linked GlcNAc transferases and proteins of the glycogen phosphorylase superfamily. / Wrabl, James O.; Grishin, Nick V.

In: Journal of Molecular Biology, Vol. 314, No. 3, 30.11.2001, p. 365-374.

Research output: Contribution to journalArticle

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abstract = "The O-linked GlcNAc transferases (OGTs) are a recently characterized group of largely eukaryotic enzymes that add a single β-N-acetylglucosamine moiety to specific serine or threonine hydroxyls. In humans, this process may be part of a sugar regulation mechanism or cellular signaling pathway that is involved in many important diseases, such as diabetes, cancer, and neurodegeneration. However, no structural information about the human OGT exists, except for the identification of tetratricopeptide repeats (TPR) at the N terminus. The locations of substrate binding sites are unknown and the structural basis for this enzyme's function is not clear. Here, remote homology is reported between the OGTs and a large group of diverse sugar processing enzymes, including proteins with known structure such as glycogen phosphorylase, UDP-GlcNAc 2-epimerase, and the glycosyl transferase MurG. This relationship, in conjunction with amino acid similarity spanning the entire length of the sequence, implies that the fold of the human OGT consists of two Rossmann-like domains C-terminal to the TPR region. A conserved motif in the second Rossmann domain points to the UDP-GlcNAc donor binding site. This conclusion is supported by a combination of statistically significant PSI-BLAST hits, consensus secondary structure predictions, and a fold recognition hit to MurG. Additionally, iterative PSI-BLAST database searches reveal that proteins homologous to the OGTs form a large and diverse superfamily that is termed GPGTF (glycogen phosphorylase/glycosyl transferase). Up to one-third of the 51 functional families in the CAZY database, a glycosyl transferase classification scheme based on catalytic residue and sequence homology considerations, can be unified through this common predicted fold. GPGTF homologs constitute a substantial fraction of known proteins: 0.4{\%} of all non-redundant sequences and about 1 {\%} of proteins in the Escherichia coli genome are found to belong to the GPGTF superfamily.",
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