Saturated long chain-FFAs, especially palmitic acid, have been implicated in apoptosis by increasing the activity of IRE1a (Inositol-requiring enzyme 1) but inhibiting the activity of PKR (double-stranded RNA-activated protein kinase).  We recently found evidence that palmitate interacts directly with the PKR, subsequently inhibiting the autophosphorylation of PKR. To further explore the opposite effects of palmitate on PKR and IRE1a activation, we performed molecular dynamics simulations to investigate possible binding modes of palmitate around kinase domain of IRE1a and PKR in the phosphorylated and unphosphorylated states, respectively. The simulation results reveal several possible binding sites for palmitate. The highest probability binding sites were further confirmed through mutational studies. Possible mechanisms are proposed for how palmitate differentially affects IRE1a/PKR activity through direct interactions.

Molecular mechanism of how palmitate affects the activity of IRE1a/PKR

246th National Meeting (2013)

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