title: The Ras-Membrane Interface: Isoform-specific Differences in The Catalytic Domain.
abstract: The small GTPase Ras is mutated in about 20% of human cancers, primarily at active site amino acid residues G12, G13, and Q61. Thus, structural biology research has focused on the active site, impairment of GTP hydrolysis by oncogenic mutants, and characterization of protein-protein interactions in the effector lobe half of the protein. The C-terminal hypervariable region has increasingly gained attention due to its importance in H-Ras, N-Ras, and K-Ras differences in membrane association. A high-resolution molecular view of the Ras-membrane interaction involving the allosteric lobe of the catalytic domain has lagged behind, although evidence suggests that it contributes to isoform specificity. The allosteric lobe has recently gained interest for harboring potential sites for more selective targeting of this elusive "undruggable" protein. The present review reveals critical insight that isoform-specific differences appear prominently at these potentially targetable sites and integrates these differences with knowledge of Ras plasma membrane localization, with the intent to better understand the structure-function relationships needed to design isoform-specific Ras inhibitors.
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts.
authors.forename: Jillian A
authors.initials: JA
authors.lastname: Parker
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts. c.mattos@neu.edu.
authors.forename: Carla
authors.initials: C
authors.lastname: Mattos
mesh_terms: D020134:Catalytic Domain; D002462:Cell Membrane / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D018631:ras Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D018631:ras Proteins