Structure and function of the DUF2233 domain in bacteria and in the human mannose 6-phosphate uncovering enzyme

Debanu Das, Wang Sik Lee, Joanna C. Grant, Hsiu Ju Chiu, Carol L. Farr, Julie Vance, Heath E. Klock, Mark W. Knuth, Mitchell D. Miller, Marc André Elsliger, Ashley M. Deacon, Adam Godzik, Scott A. Lesley, Stuart Kornfeld, Ian A. Wilson

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


DUF2233, a domain of unknown function (DUF), is present in many bacterial and several viral proteins and was also identified in the mammalian transmembrane glycoprotein N-acetylglucosamine-1-phosphodiester α-N-acetylglucosaminidase ("uncovering enzyme" (UCE)). We report the crystal structure of BACOVA-00430, a 315-residue protein from the human gut bacterium Bacteroides ovatus that is the first structural representative of the DUF2233 protein family. A notable feature of this structure is the presence of a surface cavity that is populated by residues that are highly conserved across the entire family. The crystal structure was used to model the luminal portion of human UCE (hUCE), which is involved in targeting of lysosomal enzymes. Mutational analysis of several residues in a highly conserved surface cavity of hUCE revealed that they are essential for function. The bacterial enzyme (BACOVA-00430) has ∼1% of the catalytic activity of hUCE toward the substrate GlcNAc-P-mannose, the precursor of the Man-6-P lysosomal targeting signal. GlcNAc-1-P is a poor substrate for both enzymes. We conclude that, for at least a subset of proteins in this family, DUF2233 functions as a phosphodiester glycosidase.

Original languageEnglish
Pages (from-to)16789-16799
Number of pages11
JournalJournal of Biological Chemistry
Issue number23
StatePublished - Jun 7 2013


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