The structure and conformational switching of Rap1B

• Published in: Biochemical and biophysical research communications 2015-06, Vol.462 (1), p.46-51
• Main Authors: Noguchi, Hiroki, Ikegami, Takahisa, Nagadoi, Aritaka, Kamatari, Yuji O., Park, Sam-Yong, Tame, Jeremy R.H., Unzai, Satoru
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Binding Sites - genetics; Conformation change; Crystallography, X-Ray; G protein; Guanosine Diphosphate - chemistry; Guanosine Diphosphate - metabolism; Models, Molecular; Molecular Sequence Data; Mutant; Mutation; Protein Binding; Protein crystallography; Protein Structure, Tertiary; rap GTP-Binding Proteins - chemistry; rap GTP-Binding Proteins - genetics; rap GTP-Binding Proteins - metabolism; Rap1; Rats; Sequence Homology, Amino Acid
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2015.04.103

Rap1B is a small GTPase involved in the regulation of numerous cellular processes including synaptic plasticity, one of the bases of memory. Like other members of the Ras family, the active GTP-bound form of Rap1B can bind to a large number of effector proteins and so transmit signals to downstream components of the signaling pathways. The structure of Rap1B bound only to a nucleotide has yet to be solved, but might help reveal an inactive conformation that can be stabilized by a small molecule drug. Unlike other Ras family proteins such as H-Ras and Rap2A, Rap1B crystallizes in an intermediate state when bound to a non-hydrolyzable GTP analog. Comparison with H-Ras and Rap2A reveals conservative mutations relative to Rap1B, distant from the bound nucleotide, which control how readily the protein may adopt the fully activated form in the presence of GTP. High resolution crystallographic structures of mutant proteins show how these changes may influence the hydrogen bonding patterns of the key switch residues. •Detailed structural information on Rap1B in active and inactive states is presented.•Rap1B crystallizes in an intermediate state when bound to a GTP analog.•Mutations at different sites affect the ability of Rap1 to activate appropriately.•The influence of distant parts of GTPases on the activation state is demonstrated.