Differential Inhibition of Hsc70 Activities by Two Hsc70-Binding Peptides

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Abstract
The ability of two high-affinity Hsc70-binding peptides [FYQLALT (peptide-Φ) and NIVRKKK (peptide-K)] to differentially inhibit Hsc70-dependent processes in rabbit reticulocyte lysate (RRL) was examined. Both peptide-Φ and peptide-K inhibited chaperone-dependent renaturation of luciferase in RRL. Peptide-Φ, but not peptide-K, blocked Hsp90/Hsc70-dependent transformation of the heme-regulated eIF2α kinase (HRI) into an active, heme-regulatable kinase. In contrast, peptide-K, but not peptide-Φ, inhibited Hsc70-mediated suppression of the activation of mature-transformed HRI. Furthermore, HDJ2 (Human DnaJ homologue 2), but not HDJ1, potentiated the ability of Hsc70 to suppress the activation of HRI in RRL. Mechanistically, peptide-K inhibited, while peptide-Φ enhanced, HDJ2-induced stimulation of Hsc70 ATPase activity in vitro. The data presented support the hypotheses that peptide-Φ acts to inhibit Hsc70 function by binding to the hydrophobic peptide-binding cleft of Hsc70, while peptide-K acts through binding to a site that modulates the interaction of Hsc70 with DnaJ homologues. Overall, the data indicate that peptide-Φ and peptide-K have differential effects on Hsc70 functions under quasi-physiological conditions in RRL, and suggest that therapeutically valuable peptide mimetics can be designed to inhibit specific functions of Hsc70.