Archive | 2021
PEA-15 Engages in Allosteric Interactions Using a Common Scaffold in a Phosphorylation-Dependent Manner
Abstract
\n Phosphoprotein enriched in astrocytes, 15 kDa (PEA-15) is a death-effector domain (DED) containing protein involved in regulating mitogen-activated protein kinase and apoptosis pathways. In this molecular-dynamics study, we examined how phosphorylation of the PEA-15 C-terminal tail Ser-104 and Ser-116 allosterically promotes conformational changes of the DED, and alters the binding specificity from extracellular-regulated kinase (ERK) to Fas associated death domain (FADD) protein. We found that the binding interfaces between the unphosphorylated PEA-15 and ERK2 and the doubly phosphorylated PEA-15 and FADD are similarly composed of a scaffold that includes both the DED and the C-terminal tail of PEA-15. While the unphosphorylated serine residues do not directly interact with ERK2, the phosphorylated Ser-116 engages in strong interactions with arginine residues on FADD DED. In this DED complex, FADD repositions its death domain (DD) relative to the DED, which has strong implications on the association of the death-inducing signaling complex (DISC).