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PMID:27428513

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Citation

Yu, H, Takeuchi, H, Takeuchi, M, Liu, Q, Kantharia, J, Haltiwanger, RS and Li, H (2016) Structural analysis of Notch-regulating Rumi reveals basis for pathogenic mutations. Nat. Chem. Biol. 12:735-40

Abstract

Rumi O-glucosylates the EGF repeats of a growing list of proteins essential in metazoan development, including Notch. Rumi is essential for Notch signaling, and Rumi dysregulation is linked to several human diseases. Despite Rumi's critical roles, it is unknown how Rumi glucosylates a serine of many but not all EGF repeats. Here we report crystal structures of Drosophila Rumi as binary and ternary complexes with a folded EGF repeat and/or donor substrates. These structures provide insights into the catalytic mechanism and show that Rumi recognizes structural signatures of the EGF motif, the U-shaped consensus sequence, C-X-S-X-(P/A)-C and a conserved hydrophobic region. We found that five Rumi mutations identified in cancers and Dowling-Degos disease are clustered around the enzyme active site and adversely affect its activity. Our study suggests that loss of Rumi activity may underlie these diseases, and the mechanistic insights may facilitate the development of modulators of Notch signaling.

Links

PubMed PMC4990500 Online version:10.1038/nchembio.2135

Keywords

Animals; Biocatalysis; Drosophila Proteins/chemistry; Drosophila Proteins/genetics; Drosophila Proteins/metabolism; Drosophila melanogaster/genetics; Drosophila melanogaster/metabolism; Glucosyltransferases/chemistry; Glucosyltransferases/genetics; Glucosyltransferases/metabolism; Humans; Mice; Mutation; Protein Conformation

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DROME:RUMI

enables

GO:0035251: UDP-glucosyltransferase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

DROME:RUMI

involved_in

GO:0018242: protein O-linked glycosylation via serine

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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