Genetic analyses uncover pleiotropic compensatory roles for Drosophila Nucleobindin-1 in inositol trisphosphate-mediated intracellular calcium homeostasis
| Autor: | Bharath Srinivasan, Vidhya Balasubramanian |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cell type biology ved/biology ved/biology.organism_classification_rank.species Mutant Inositol trisphosphate General Medicine Inositol trisphosphate receptor biology.organism_classification Phenotype Cell biology 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine chemistry Genetics Inositol Drosophila melanogaster Model organism Molecular Biology 030217 neurology & neurosurgery Biotechnology |
| Zdroj: | Genome. 63:61-90 |
| ISSN: | 1480-3321 0831-2796 |
| Popis: | Nucleobindin-1 is an EF-hand calcium-binding protein with a distinctive profile, predominantly localized to the Golgi in insect and wide-ranging vertebrate cell types, alike. Its putative involvements in intracellular calcium (Ca2+) homeostasis have never been phenotypically characterized in any model organism. We have analyzed an adult-viable mutant that completely disrupts the G protein α-subunit binding and activating (GBA) motif of Drosophila Nucleobindin-1 (dmNUCB1). Such disruption does not manifest any obvious fitness-related, morphological/developmental, or behavioral abnormalities. A single copy of this mutation or the knockdown of dmnucb1 in restricted sets of cells variously rescues pleiotropic mutant phenotypes arising from impaired inositol 1,4,5-trisphosphate receptor (IP3R) activity (in turn depleting cytoplasmic Ca2+ levels across diverse tissue types). Additionally, altered dmNUCB1 expression or function considerably reverses lifespan and mobility improvements effected by IP3R mutants, in a Drosophila model of amyotrophic lateral sclerosis. Homology modeling-based analyses further predict a high degree of conformational conservation in Drosophila, of biochemically validated structural determinants in the GBA motif that specify in vertebrates, the unconventional Ca2+-regulated interaction of NUCB1 with Gαi subunits. The broad implications of our findings are hypothetically discussed, regarding potential roles for NUCB1 in GBA-mediated, Golgi-associated Ca2+ signaling, in health and disease. |
| Databáze: | OpenAIRE |
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