Molecular mechanism of G protein activation by GIV, a protein that promotes metastasis

The insufficient mechanistic information on metastasis has precluded the development of efficient therapeutics for fighting this process. However, the Gα-Interacting, Vesicle-associtated (GIV) protein has emerged as a very promising candidate to become one of the “master regulators” of metastasis. Therefore, its characterization may open new avenues for therapeutic intervention.

By a combination of biochemical and structural techniques, including NMR, a team of researchers has uncovered the molecular mechanism behind GIV binding and subsequent activation of a G protein. G proteins are components of the complex communication system that the body uses to sense hormones in the bloodstream and to send the corresponding messages to cells.

The results show that the mode of action of GIV differs from that described for the well known GPCR proteins. In fact, it binds to a different region. The obtained molecular modelling and NMR data have permitted to deduce the protein-protein interface and to show that GIV binds to a cavity on the surface of the G protein. These results suggest the existence of an allosteric regulation mechanism: the conformational changes that take place at one protein G site propagate to another distant site in the molecule.

The work has been the result of a close collaboration between the group of Mikel García-Marcos at Boston University and the group of Francisco J Blanco at CIC bioGUNE, and has been published in the journal Nature Communications.

The synergy between the two teams, together with the participation or researchers from IRB Barcelona, Cornell University, and the University of Glasgow has made it possible to uncover this novel mode of action of a G protein regulator. Multidisciplinary studies of this kind are key to characterize the complex biological processes relevant in biomedical cancer research.

About CIC bioGUNE

The Centre for Cooperative Research in Biosciences (CIC bioGUNE), located in the Bizkaia Technology Park, is a biomedical research organisation conducting cutting-edge research at the interface between structural, molecular and cell biology, with a particular focus on the study of the molecular basis of disease, for use in the development of new diagnostic methods and advanced therapies.

Reference:
Molecular mechanism of Gαi activation by non-GPCR proteins with a Gα-Binding and Activating motif. A Ibáñez de Opakua, K Parag-Sharma, V DiGiacomo, N Merino, A Leyme, A Marivin, M Villate, LT Nguyen, MA de la Cruz-Morcillo, JB Blanco-Canosa, S Ramachandran, George S Baillie, RA Cerione, FJ Blanco, M Garcia-Marcos (2017) Nature Commun 8, 13935.

Figure:
Representation of the molecular model of the G protein bound to a GIV fragment (green ribbon and coil). The surface of the G protein is colored based on the NMR signal perturbations.