RRC ID 74677
Author Nurmahdi H, Hasegawa M, Mujizah EY, Sasamura T, Inaki M, Yamamoto S, Yamakawa T, Matsuno K.
Title Notch Missense Mutations in Drosophila Reveal Functions of Specific EGF-like Repeats in Notch Folding, Trafficking, and Signaling.
Journal Biomolecules
Abstract Notch signaling plays various roles in cell-fate specification through direct cell-cell interactions. Notch receptors are evolutionarily conserved transmembrane proteins with multiple epidermal growth factor (EGF)-like repeats. Drosophila Notch has 36 EGF-like repeats, and while some play a role in Notch signaling, the specific functions of most remain unclear. To investigate the role of each EGF-like repeat, we used 19 previously identified missense mutations of Notch with unique amino acid substitutions in various EGF-like repeats and a transmembrane domain; 17 of these were identified through a single genetic screen. We assessed these mutants' phenotypes in the nervous system and hindgut during embryogenesis, and found that 10 of the 19 Notch mutants had defects in both lateral inhibition and inductive Notch signaling, showing context dependency. Of these 10 mutants, six accumulated Notch in the endoplasmic reticulum (ER), and these six were located in EGF-like repeats 8-10 or 25. Mutations with cysteine substitutions were not always coupled with ER accumulation. This suggests that certain EGF-like repeats may be particularly susceptible to structural perturbation, resulting in a misfolded and inactive Notch product that accumulates in the ER. Thus, we propose that these EGF-like repeats may be integral to Notch folding.
Volume 12(12)
Published 2022-11-25
DOI 10.3390/biom12121752
PII biom12121752
PMID 36551180
PMC PMC9775759
MeSH Animals Drosophila / genetics Drosophila / metabolism Drosophila Proteins* / genetics Drosophila Proteins* / metabolism Epidermal Growth Factor* / chemistry Epidermal Growth Factor* / genetics Mutation, Missense Receptors, Notch / genetics Receptors, Notch / metabolism
IF 4.082
Drosophila DGRC#116669 DGRC#116715 DGRC#116750 DGRC#116605 DGRC#116608 DGRC#116671 DGRC#116689 DGRC#116597 DGRC#116684 DGRC#116700 DGRC#116625 DGRC#116732 DGRC#116764 DGRC#116573