Molecular mechanism by which palmitate inhibits PKR autophosphorylation

Hyunju Cho, Shayantani Mukherjee, Pratheeba Palasuberniam, Lisa Pillow, Betul Bilgin, Catherine Nezich, S. Patrick Walton, Michael Feig, Christina Chan

    Research output: Research - peer-reviewArticle

    • 3 Citations

    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.

    LanguageEnglish (US)
    Pages1110-1119
    Number of pages10
    JournalBiochemistry
    Volume50
    Issue number6
    DOIs
    StatePublished - Feb 15 2011

    Profile

    Palmitates
    Phosphotransferases
    Adenosine Triphosphate
    Binding Sites
    Proteins
    eIF-2 Kinase
    Double-Stranded RNA
    Innate Immunity
    Antiviral Agents
    Fatty Acids
    Phosphorylation
    Apoptosis
    Drug Therapy
    Mutation
    Drug therapy

    ASJC Scopus subject areas

    • Biochemistry

    Cite this

    Cho, H., Mukherjee, S., Palasuberniam, P., Pillow, L., Bilgin, B., Nezich, C., ... Chan, C. (2011). Molecular mechanism by which palmitate inhibits PKR autophosphorylation. Biochemistry, 50(6), 1110-1119. DOI: 10.1021/bi101923r

    Molecular mechanism by which palmitate inhibits PKR autophosphorylation. / Cho, Hyunju; Mukherjee, Shayantani; Palasuberniam, Pratheeba; Pillow, Lisa; Bilgin, Betul; Nezich, Catherine; Walton, S. Patrick; Feig, Michael; Chan, Christina.

    In: Biochemistry, Vol. 50, No. 6, 15.02.2011, p. 1110-1119.

    Research output: Research - peer-reviewArticle

    Cho, H, Mukherjee, S, Palasuberniam, P, Pillow, L, Bilgin, B, Nezich, C, Walton, SP, Feig, M & Chan, C 2011, 'Molecular mechanism by which palmitate inhibits PKR autophosphorylation' Biochemistry, vol 50, no. 6, pp. 1110-1119. DOI: 10.1021/bi101923r
    Cho H, Mukherjee S, Palasuberniam P, Pillow L, Bilgin B, Nezich C et al. Molecular mechanism by which palmitate inhibits PKR autophosphorylation. Biochemistry. 2011 Feb 15;50(6):1110-1119. Available from, DOI: 10.1021/bi101923r
    Cho, Hyunju ; Mukherjee, Shayantani ; Palasuberniam, Pratheeba ; Pillow, Lisa ; Bilgin, Betul ; Nezich, Catherine ; Walton, S. Patrick ; Feig, Michael ; Chan, Christina. / Molecular mechanism by which palmitate inhibits PKR autophosphorylation. In: Biochemistry. 2011 ; Vol. 50, No. 6. pp. 1110-1119
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