Kelch-like ECH-associated protein 1-Phosphoglycerate mutase family member 5 protein-protein interface (Keap1-PGAM5 interface)

The Kelch-like ECH-associated protein 1-Phosphoglycerate mutase family member 5 (Keap1-PGAM5) protein-protein interface is a regulatory hub connecting the Keap1-Nrf2 antioxidant pathway with mitochondrial quality control (UniProt Q14145, Q96HS1). Keap1 typically acts as a substrate adapter for the Cullin 3-based E3 ubiquitin ligase, targeting Nrf2 for degradation, but it also binds PGAM5, a mitochondrial phosphatase, through a conserved NXESGE motif in the PGAM5 N-terminus (Lo & Hannink, 2006, PubMed: 16959778). This interaction anchors Keap1 to the outer mitochondrial membrane, which can sequester Keap1 away from Nrf2 or facilitate the degradation of PGAM5 itself, thereby regulating mitophagy and necroptosis (Sadatomi et al., 2013, PubMed: 23532841). Dysregulation of this interface is linked to neurodegenerative disorders like Parkinson's disease and various cancers, where it influences cell survival under oxidative stress. Pharmacological modulation of this interface is an emerging area of research, with experimental small molecules and peptide mimetics being developed to disrupt the binding and restore mitochondrial or redox homeostasis. Targeting this specific interaction offers a potential strategy to fine-tune the antioxidant response without the broad effects of global Keap1 inhibition. Current research focuses on identifying high-affinity ligands for the Keap1 Kelch domain that specifically compete with PGAM5 (Panda et al., 2020, PubMed: 32663374).

Other names

Keap1-PGAM5 complexKeap1-PGAM5 interactionPGAM5-Keap1 interface

Competitive inhibition of the Keap1 Kelch domain to prevent its association with the PGAM5 NXESGE motif, thereby modulating mitochondrial sequestration of Keap1 and downstream Nrf2 or mitophagy signaling.