Long-lasting salt bridges provide the anchoring mechanism of oncogenic KRas-4B at cell membranes [article]

Huixia Lu, Jordi Marti
2020 bioRxiv   pre-print
Ras is a family of related proteins participating in all animal cell lineages and organs which work as GDP-GTP binary switches and regulate cytoplasmic signalling networks able to control several cellular processes, playing an essential role in signal transduction pathways involved in cell growth, differentiation and survival. In this work, a G12D mutated farnesylated GTP bound KRas-4B protein has been simulated at the interface of a DOPC/DOPS/cholesterol model anionic cell membrane at the
more » ... tom level. A specific long-lasting salt bridge connection between farnesyl and the hypervariable region of the protein has been identified as the main mechanism responsible of the binding of oncogenic farnesylated KRas-4B to the cell membrane, since this particular bond is absent in both wild-type and oncogenic methylated species of KRas-4B. This finding may lead to a deeper understanding of the mechanisms of protein binding and eventual growing and spreading inside cell membranes. From free energy landscapes obtained by well-tempered metadynamics simulations, we have characterised local and global minima of KRas-4B binding and revealed the main pathways between anchored and released states.
doi:10.1101/2020.08.14.250738 fatcat:igy77yrbkbgb3pqih2eqrli4yi