RRC ID 57686
Author Balasubramanian V, Srinivasan B.
Title Genetic analyses uncover pleiotropic compensatory roles for Drosophila Nucleobindin-1 in inositol trisphosphate-mediated intracellular calcium homeostasis.
Journal Genome
Abstract 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.
Volume 63(2)
Pages 61-90
Published 2020-2-1
DOI 10.1139/gen-2019-0113
PMID 31557446
MeSH Alleles Amino Acid Motifs Animals Calcium / metabolism* Calcium-Binding Proteins / chemistry Calcium-Binding Proteins / genetics Calcium-Binding Proteins / metabolism Calcium-Binding Proteins / physiology* DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism Drosophila Proteins / chemistry Drosophila Proteins / genetics Drosophila Proteins / metabolism Drosophila Proteins / physiology* Drosophila melanogaster / genetics Drosophila melanogaster / growth & development Drosophila melanogaster / metabolism GTP-Binding Protein alpha Subunits / metabolism Genes, Lethal Genetic Pleiotropy Golgi Apparatus / metabolism Homeostasis Humans Inositol 1,4,5-Trisphosphate / metabolism Inositol 1,4,5-Trisphosphate Receptors / genetics* Mutation Nucleobindins / chemistry Nucleobindins / genetics Nucleobindins / metabolism Nucleobindins / physiology* Protein Domains Structural Homology, Protein
IF 2.037
Times Cited 0