The deviant Ras activation machinery is found in approximately 30% of all human
cancers. SOS1 is an important protagonist of this pathway that plays a key-role
in aberrant cell proliferation and differentiation. Interaction of SOS1 with
14-3-3 proteins modulates SOS1 activity in Ras-MAPK signaling. In the present
study, we analyze the 14-3-3/SOS1 protein-protein interaction (PPI) by different
biochemical assays and report the high resolution crystal structure of a 13-mer
motif of SOS1 bound to 14-3-3ζ. These structural and functional insights are
important for the evaluation of this PPI interface for small-molecule
stabilization as a new starting point for modulating the Ras-Raf-MAPK pathway.