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HCF-1 Is Cleaved in the Active Site of O-GlcNAc Transferase

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Science  06 Dec 2013:
Vol. 342, Issue 6163, pp. 1235-1239
DOI: 10.1126/science.1243990

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Dual-Duty Active Site

O-linked N-acetylglucosamine transferase (OGT) catalyzes the addition of N-acetylglucosamine (GlcNac) to serine or threonine residues, influencing the localization and function of proteins. Because its activity is sensitive to the nutrient uridine diphosphate (UDP)–GlcNac, OGT has been proposed to regulate cellular responses to nutrient status. Recently, OGT in the presence of UDP-GlcNac was shown to cleave host cell factor–1 (HCF-1), a transcriptional coregulator of human cell-cycle progression. This cleavage is required for HCF-1 maturation. Through a combination of structural, biochemical, and mutagenesis studies, Lazarus et al. (p. 1235) show that both cleavage and glycosylation of HCF-1 occur in the OGT active site. Cleavage occurs between cysteine and glutamine and converts the glutamine into a serine which can then be glycosylated.

Abstract

Host cell factor–1 (HCF-1), a transcriptional co-regulator of human cell-cycle progression, undergoes proteolytic maturation in which any of six repeated sequences is cleaved by the nutrient-responsive glycosyltransferase, O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT). We report that the tetratricopeptide-repeat domain of O-GlcNAc transferase binds the carboxyl-terminal portion of an HCF-1 proteolytic repeat such that the cleavage region lies in the glycosyltransferase active site above uridine diphosphate–GlcNAc. The conformation is similar to that of a glycosylation-competent peptide substrate. Cleavage occurs between cysteine and glutamate residues and results in a pyroglutamate product. Conversion of the cleavage site glutamate into serine converts an HCF-1 proteolytic repeat into a glycosylation substrate. Thus, protein glycosylation and HCF-1 cleavage occur in the same active site.

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