title: Molecular mechanism by which palmitate inhibits PKR autophosphorylation.
abstract: PKR (double-stranded RNA-activated protein kinase) is an important component of the innate immunity, antiviral, and apoptotic pathways. Recently, our group found that palmitate, a saturated fatty acid, is involved in apoptosis by reducing the autophosphorylation of PKR at the Thr451 residue; however, the molecular mechanism by which palmitate reduces PKR autophosphorylation is not known. Thus, we investigated how palmitate affects the phosphorylation of the PKR protein at the molecular and biophysical levels. Biochemical and computational studies show that palmitate binds to PKR, near the ATP-binding site, thereby inhibiting its autophosphorylation at Thr451 and Thr446. Mutation studies suggest that Lys296 and Asp432 in the ATP-binding site on the PKR protein are important for palmitate binding. We further confirmed that palmitate also interacts with other kinases, due to the conserved ATP-binding site. A better understanding of how palmitate interacts with the PKR protein, as well as other kinases, could shed light onto possible mechanisms by which palmitate mediates kinase signaling pathways that could have implications on the efficacy of current drug therapies that target kinases.
authors.affiliation: Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, Michigan 48824, United States.
authors.forename: Hyunju
authors.initials: H
authors.lastname: Cho
authors.forename: Shayantani
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Pratheeba
authors.initials: P
authors.lastname: Palasuberniam
authors.forename: Lisa
authors.initials: L
authors.lastname: Pillow
authors.forename: Betul
authors.initials: B
authors.lastname: Bilgin
authors.forename: Catherine
authors.initials: C
authors.lastname: Nezich
authors.forename: S Patrick
authors.initials: SP
authors.lastname: Walton
authors.forename: Michael
authors.initials: M
authors.lastname: Feig
authors.forename: Christina
authors.initials: C
authors.lastname: Chan
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D007700:Kinetics; D008958:Models, Molecular; D009154:Mutation; D010168:Palmitates / Q000737:chemistry* / Q000494:pharmacology*; D010766:Phosphorylation; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D010168:Palmitates; D000255:Adenosine Triphosphate; D019892:eIF-2 Kinase