RRC ID |
74677
|
Author |
Nurmahdi H, Hasegawa M, Mujizah EY, Sasamura T, Inaki M, Yamamoto S, Yamakawa T, Matsuno K.
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Title |
Notch Missense Mutations in Drosophila Reveal Functions of Specific EGF-like Repeats in Notch Folding, Trafficking, and Signaling.
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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.
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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
|
Resource |
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 |