Abstract 4373: Structural basis of recognition of farnesylated and methylated KRAS4b by PDEδ

KRAS is the most frequently mutated member of RAS superfamily in all human cancers. Post-translational farnesylation and methylation of KRAS at its C-terminal end plays an important role in its trafficking to proper subcellular compartments for cell signaling events. PDEδ acts as a chaperone for farnesylated members of the RAS superfamily and plays a key role in their trafficking from the place of biosynthesis or post-translational modification to a transport vesicle or plasma membrane. We solved the structures of wild-type full-length KRAS4b (farnesylated and methylated) in complex with PDEδ in two different crystal forms at 2 Ang resolution. Our structure showed that only the last six amino acids of hypervariable region (and not the G-domain) of KRAS4b interact with PDEδ. Farnesyl and methyl groups present on Cys185 bind tightly in the central hydrophobic pocket present in PDEδ. In crystal form II, we could see all amino acids present in the hypervariable region of KRAS4b, thus providing atomic details of hypervariable region of KRAS4b for the first time. Comparison of the two crystal forms suggests how PDEδ could bind to both farnesylated as well as geranylgeranylated KRAS4b. The structure provides the rationale for nucleotide-independent binding of KRAS4b to PDEδ and its interaction with other farnesylated but not palmitoylated members of RAS superfamily. Citation Format: Sathiya Dharmaiah, Lakshman Bindu, Peter Frank, William Gillette, Dominic Esposito, Dwight Nissley, Frank McCormick, Andrew Stephen, Dhirendra Simanshu. Structural basis of recognition of farnesylated and methylated KRAS4b by PDEδ. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4373.