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Nat Chem Biol. 2016 Sep;12(9):735-40. doi: 10.1038/nchembio.2135. Epub 2016 Jul 18.

Structural analysis of Notch-regulating Rumi reveals basis for pathogenic mutations.

Author information

1
Biology Department, Brookhaven National Laboratory, Upton, New York, USA.
2
Complex Carbohydrate Research Center, the University of Georgia, Athens, Georgia, USA.
3
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, USA.

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.

PMID:
27428513
PMCID:
PMC4990500
DOI:
10.1038/nchembio.2135
[Indexed for MEDLINE]
Free PMC Article

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