KRas–Calmodulin protein–protein interface (KRas–CaM PPI)

The KRas–Calmodulin protein–protein interface is a specialized regulatory interaction between the KRas4B isoform and the calcium-sensing protein Calmodulin (CaM). Calmodulin binds to the farnesylated C-terminal hypervariable region (HVR) of KRas4B in a calcium-dependent manner, a process that regulates the spatial distribution of KRas between the plasma membrane and internal compartments (PubMed: 21813641). This interaction is particularly significant in the context of cancer, as KRas4B is the most frequently mutated oncogene in human malignancies, including pancreatic, colorectal, and lung cancers (PubMed: 28341615). By binding to KRas4B, Calmodulin can sequester the protein from the membrane or modulate its ability to activate downstream effectors like PI3K and Raf-1, thereby influencing cell proliferation and survival pathways (PubMed: 30655301). Therapeutic targeting of this interface aims to disrupt KRas-driven signaling by preventing the proper localization and assembly of KRas signaling complexes. While several small molecules and natural products like Ophiobolin A have been shown to interfere with this interaction in preclinical models, the primary challenge remains achieving selectivity to avoid interfering with Calmodulin's broad range of essential physiological functions (PubMed: 26039112).

Other names

KRas-CaM interfaceKRas4B-Calmodulin interactionKRas-Calmodulin complexK-Ras4B:CaM interface

Inhibition of the protein-protein interaction between Calmodulin and the farnesylated hypervariable region of KRas4B, leading to KRas mislocalization and reduced downstream signaling.