Ras proteins are signal-transducing GTPases that cycle between inactive GDP-bound and active GTP-bound forms. Ras is a prolific signaling molecule interacting with a spectrum of effector molecules and acting through more than one signaling pathway. The Ras-effector proteins contain a Ras-associating (RA) domain through which these associate with Ras in a GTP-dependent manner. The RA domain is highly conserved among the members of the growth factor receptor-bound (Grb) 7 family of proteins which includes Grb7, Grb10 and Grb14. Our laboratory has reported an unusual observation that RA domain of Grb14 binds to the C-terminal nucleotide binding site of cyclic nucleotide gated channel (CTRCNGA1) and inhibits the channel activity. Molecular modeling of the CTR-CNGA1 displays 50%-70% tertiary structural similarity towards Ras proteins. We named this region as Ras-like domain (RLD). The interaction between RA-Grb14 and RLD-CNGA1 is mediated through a simple protein-protein interaction temporally and spatially regulated by light and cGMP. It is interesting to note that Grb14 binds to GTPase-mutant Rab5, a Ras-related small GTPase whereas Grb10 binds only to GTP-bound form of active Rab5 but not to GTPase-defective mutant Rab5. These results suggest that Grb14 might have been evolved later in the evolution that binds to both Ras and nucleotide binding proteins such as CNGA1. Our studies also suggest that eukaryotic CNG channels could be evolved through a gene fusion between prokaryotic ion channels and cyclic nucleotide binding proteins, both of which might have undergone several sequence variations for functional adaptation during evolution.
Amino Acid Sequence ; Animals ; Cattle ; Cell Membrane ; metabolism ; radiation effects ; Conserved Sequence ; Cyclic Nucleotide-Gated Cation Channels ; genetics ; metabolism ; Evolution, Molecular ; Female ; GRB7 Adaptor Protein ; chemistry ; genetics ; metabolism ; HEK293 Cells ; Humans ; Light ; Male ; Models, Molecular ; Molecular Sequence Data ; Protein Binding ; radiation effects ; Protein Structure, Tertiary ; Protein Transport ; Rats ; Rod Cell Outer Segment ; radiation effects ; rab5 GTP-Binding Proteins ; metabolism ; ras Proteins ; metabolism