Protein kinase C delta (PKCδ) – Receptor for activated C kinase (RACK) interface (PKCδ-RACK interface)

The Protein kinase C delta (PKCδ) – Receptor for activated C kinase (RACK) interface is a specialized protein-protein interaction site essential for the spatial regulation of PKCδ signaling (Mochly-Rosen et al., 2012, Nature Reviews Drug Discovery). PKCδ is a member of the novel PKC subfamily that plays a dual role in cell survival and apoptosis depending on its subcellular localization (Inagaki et al., 2003, Circulation). The interaction with RACK proteins facilitates the translocation of activated PKCδ to specific compartments like the mitochondria, where it can promote pro-apoptotic signaling during ischemia-reperfusion injury (Churchill et al., 2008, Annual Review of Pharmacology and Toxicology). Because the RACK-binding site is distinct for each PKC isoform, targeting this interface allows for the development of highly selective inhibitors, such as the peptide delcasertib (KAI-9803), which avoids the off-target effects common to ATP-competitive kinase inhibitors (Bates et al., 2008, Journal of the American College of Cardiology). This interface has been a major focus in cardiovascular research, particularly for reducing infarct size during myocardial infarction, and is also investigated in oncology and neuroprotection (Palaniyandi et al., 2009, Cardiovascular Research). Successful modulation of this interface prevents the detrimental effects of PKCδ activation while sparing the cytoprotective functions of other isoforms like PKCε.

Other names

PKC delta-RACK interactionPRKCD-RACK1 interfaceδV1-1 binding sitePKCδ-RACK complex

Inhibition of protein-protein interaction to prevent isoform-specific translocation of Protein kinase C delta to its functional sites.