Cytoplasmic tail of the Receptor for Advanced Glycation End-products–Diaphanous-related formin 1 protein–protein interface (ctRAGE–DIAPH1 interface)

The cytoplasmic tail of the Receptor for Advanced Glycation End-products (ctRAGE)–Diaphanous-related formin 1 (DIAPH1) protein–protein interface is a critical intracellular signaling node. RAGE is a multi-ligand pattern recognition receptor, and its cytoplasmic tail is essential for transducing signals from ligands like advanced glycation end-products (AGEs) and S100 proteins (Hudson & Schmidt, 2022, Nature Reviews Endocrinology). DIAPH1, a member of the formin family, binds directly to ctRAGE, a step required for the activation of Rho GTPases (such as Cdc42 and Rac1) and the subsequent activation of the NF-κB pathway (Manigrasso et al., 2016, Nature Communications). This signaling axis plays a pivotal role in the pathogenesis of diabetic complications, including nephropathy and cardiovascular disease, by promoting chronic inflammation and vascular damage (Juranek et al., 2015). Therapeutic targeting of this interface using small molecules like RAGE229 has shown promise in preclinical models by specifically disrupting the ctRAGE–DIAPH1 interaction without affecting the extracellular ligand-binding domain of RAGE (Rai et al., 2020, JBC). This approach offers a highly specific method to mitigate RAGE-driven pathology while potentially avoiding the broad systemic effects of total RAGE or DIAPH1 inhibition.

Other names

RAGE-DIAPH1 interactionctRAGE-mDia1 complexRAGE-mDia1 signaling axisAGER-DIAPH1 interface

Small molecule competitive inhibition of the protein-protein interaction between the RAGE cytoplasmic tail and the DIAPH1 FH1 domain.