title: Ca2+ -myristoyl switch in neuronal calcium sensor-1: a role of C-terminal segment.
abstract: NCS1 (neuronal calcium sensor-1) is a Ca(2+)-myristoyl switch protein of the NCS protein family involved in synaptic plasticity and neurotransmission via Ca(2+)-dependent regulation of dopamine D2 receptor and associated Gprotein coupled receptor kinase (GRK)-2. Overexpression of NCS1 in synaptic terminals results in accumulation of membrane-bound protein and its redundant regulatory activity associated with neurological disorders. Here, we have demonstrated that bovine photoreceptors contain NCS1 that is capable of a partially irreversible interaction with isolated photoreceptor membranes and implicated in Ca(2+)-dependent binding and regulation of GRK1 in vitro. Using NCS1- recoverin C-terminal chimeric construct (NR), it was found that the Ca(2+)-myristoyl switch of NCS1 is affected by its C-terminal segment downstream the fourth EF-loop of the protein, which is variable within the NCS family. NR retains structural stability and sensitivity to Ca(2+), but interacts with photoreceptor membranes with lower affinity in a Ca(2+)- dependent fully reversible manner and displays altered GRK1 modulation. These data combined with fluorescent probing of surface hydrophobicity of NCS1, NR and recoverin suggest that the C-terminal segment of NCS1 regulates reuptake of myristoyl group under Ca(2+)-free conditions and participates in organization of the target-binding pocket of the protein. We point out a putative role of NCS1 in photoreceptors as a modulator of GRK activity and propose targeting of the C-terminal segment of NCS1 as an appropriate way for selective suppression of excessive membrane accumulation and aberrant activity of the protein in neurons associated with central nervous system dysfunctions.
authors.forename: Viktoriia E
authors.initials: VE
authors.lastname: Baksheeva
authors.forename: Aliya A
authors.initials: AA
authors.lastname: Nazipova
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Zinchenko
authors.forename: Marina V
authors.initials: MV
authors.lastname: Serebryakova
authors.forename: Ivan I
authors.initials: II
authors.lastname: Senin
authors.forename: Sergei E
authors.initials: SE
authors.lastname: Permyakov
authors.forename: Pavel P
authors.initials: PP
authors.lastname: Philippov
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Zamyatnin
authors.affiliation: A.N. Belozersky Institute of Physico-Chemical Biology MSU, 119992 Leninskye gory 1, b. 40, Moscow, Russia. zerni@belozersky.msu.ru.
authors.forename: Evgeni Y
authors.initials: EY
authors.lastname: Zernii
authors.forename: Gjumrakch
authors.initials: G
authors.lastname: Aliev
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D051606:G-Protein-Coupled Receptor Kinase 1 / Q000378:metabolism; D051580:Neuronal Calcium-Sensor Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010786:Photoreceptor Cells / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D051580:Neuronal Calcium-Sensor Proteins; D017382:Reactive Oxygen Species; D051606:G-Protein-Coupled Receptor Kinase 1; D002118:Calcium