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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Yu, Hongjun, Takeuchi, Hideyuki, Takeuchi, Megumi, Liu, Qun, Kantharia, Joshua, Haltiwanger, Robert S., Li, Huilin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990500/
https://www.ncbi.nlm.nih.gov/pubmed/27428513
http://dx.doi.org/10.1038/nchembio.2135
Descripción
Sumario: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 or 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.