GAB2 - Structure

Structure

GAB2 is a large multi-site docking protein (LMD) of about 100kD which has a folded N-terminal domain attached to an extended, disordered C-terminal tail rich in short linear motifs. LMDs are docking proteins which function as platforms mediating interaction between different signaling pathways and assisting with signal integration. The N-terminal is characterized by a Pleckstrin Homology (PH) domain that is the most highly conserved region between all members of the GAB family of proteins. (GAB1, GAB2, GAB3 and GAB4) GAB2 is an Intrinsically disordered protein, meaning that beyond the folded N-terminal region, the C-terminal region extends out into the cytoplasm with little or no secondary structure. The disordered region of the protein however may not be as disordered as was initially expected, as sequencing has revealed significant similarity between the “disordered” regions of GAB orthologs in different species.

The PH domain of GAB2 recognizes phosphatidylinositol 3,4,5-triphosphate(PIP3) in the membrane and is responsible for localizing the GAB protein on the intracellular surface of the membrane and in regions where the cell contacts another cell. Some evidence also suggests that the PH domain plays a role in some signal regulation as well.

Adjacent to the PH domain is a central, proline rich domain which contains many PXXP motifs for binding to the SH3 domains of signaling molecules such as Grb2 (from which the name “Grb2 associated binding” protein, GAB, comes). It is hypothesized that binding sites in this region may be used in indirect mechanisms pairing the GAB2 protein to receptor tyrosine kinases. It is on the C-terminal tail that the various conserved protein binding motifs and phosphorylation sites of GAB2 are found. GAB2 binds to the SH2 domains of such signaling molecules as SHP2 and PI3K. By binding to the p85 subunit of PI3K, and continuing this signaling pathway GAB provides positive feedback for the creation of PIP3, produced as a result of the PI3K pathway which binds to GAB2 in the membrane and promotes activation of more PI3Ks. Discovery of multiple binding sites in GAB proteins has led to the N-terminal folding nucleation (NFN) hypothesis for the structure of the disordered region. This theory suggests that the disordered domain is looped back to connect to the N-terminal, structured region several times to make the protein more compact. This would assist in promoting interactions between molecules bound to GAB and resisting degradation.