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: Contribution to journalArticle

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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
eIF-2 Kinase
Drug therapy
Phosphorylation
Proteins
Double-Stranded RNA
Innate Immunity
Antiviral Agents
Fatty Acids
Apoptosis
Drug Therapy
Mutation

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: Contribution to journalArticle

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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