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Stochasticity Open Seminar May 16, 2017, 12:00

Open Seminars of the Research Group on


Stochasticity and Control in the Dynamics and Diversity of Immune Repertories: an Example of Multi-Cellular Co-Operation


Tuesday, May 16, 2017, 12:00

at the Israel Institute for Advanced Studies, Room 128



Deciphering the structural design principles for interaction specificity among signaling proteins


Mickey Kosloff (Haifa U)


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 “code” for such selectivity 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. Of particular interest to our lab are the ubiquitous protein super-families involved in G protein coupled signaling and tyrosine kinase dependent signaling.
We developed a “bottom-up” approach that utilizes energy calculations of multiple 3D structures to decipher interaction specificity. We integrate these calculations with biochemical and biophysical results 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.


Related Research Questions


  1. How do structurally-similar proteins encode for common function yet different specificities?
  2. How do structurally-dissimilar proteins encode for similar specificities for a common target?
  3. How does specificity “wire” together signaling networks?


Suggested Reading


Integrating energy calculations with functional assays to decipher the specificity of G protein-RGS protein interactions.
Kosloff M, Travis AM, Bosch DE, Siderovski DP, Arshavsky VY.
From Protein Structure to Function via Computational Tools and Approaches
Rachel Kolodny, Mickey Kosloff


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