Protein kinase C C1 domain (C1 domain)

The Protein kinase C (PKC) C1 domain is a conserved, cysteine-rich regulatory module of approximately 50 amino acids that serves as the primary sensing site for the second messenger diacylglycerol (DAG) (Newton, A. C., 2018, Chemical Reviews). Found in conventional and novel PKC isoforms, this domain coordinates two zinc ions and possesses a hydrophobic groove that accommodates DAG or exogenous ligands such as phorbol esters and bryostatins (Igomenova, T. I., 2015, Biochemistry). Upon ligand binding, the C1 domain facilitates the translocation of the PKC enzyme from the cytosol to the plasma membrane, a critical step in the activation of various intracellular signaling pathways. This recruitment triggers a conformational change that releases the kinase's autoinhibitory pseudosubstrate, allowing for substrate phosphorylation and downstream signaling (Kourani et al., 2022, Frontiers in Drug Discovery). Because PKC signaling regulates vital processes such as cell growth, apoptosis, and synaptic plasticity, the C1 domain is a significant therapeutic target for conditions like cancer and Alzheimer's disease. Drugs targeting this domain, such as bryostatin-1 and ingenol mebutate, work by modulating PKC activity, though achieving isoform specificity remains a major challenge in drug development.

Other names

C1 regionCysteine-rich domainDAG-binding domainPhorbol ester binding site

Ligands bind to the C1 domain to mimic the natural activator diacylglycerol (DAG), inducing membrane translocation and allosteric activation of the kinase by releasing the pseudosubstrate.