Deciphering the Design Principals for Interaction Specificity between Signaling Proteins

For cellular signaling cascades to function correctly, their protein components must recognize their appropriate partners accurately. This requirement presents a challenge for living cells, as related components are used repeatedly in both parallel and intersecting cascades within the same cell. Signaling therefore requires that the interactions of particular protein-family members be tailored to each signaling cascade via interaction specificity. Understanding the structural basis for such selective molecular recognition is a major goal in both experimental and computational biology, as well as in drug design. Yet, beyond single representative examples, little is known of how specificity is determined among members of large protein families, including those involved in signal transduction.

We developed a “bottom-up” approach that utilizes energy calculations of multiple 3D structures to decipher interaction specificity. We integrate these calculations with experimental measurements to map specificity determinants at the protein family level and at the resolution of individual amino acids. The resulting “residue-level maps” are then used to redesign proteins with altered activities and specificities, offering new insights into protein-protein interactions. This also paves the way for the engineering of signaling networks at the cellular level and for developing better drugs that take family-level specificity into account.