Src Homology 2 (SH2) domains represent the largest class of known phosphotyrosine (pTyr)-recognition domains.  Taking advantage of its highly evolvable binding pocket, we seek to engineer SH2 domain to recognize sulfotyrosine (sTyr), an analog of pTyr.  sTyr is a product of protein tyrosine <i>O</i>-sulfation, the most common type of tyrosine modification in nature.  The introduction of negatively charged sulfate group onto tyrosine residues plays crucial roles in extracellular biomolecular interactions that dictate various cellular processes including cell adhesion, leukocyte trafficking, hormone activities, and immune responses.  By using phage display, we successfully identified SH2 domain mutants with significantly enhanced affinity towards sTyr.  These evolved SH2 domain mutants can be used as “anti-sTyr antibody-mimetic” with the advantages of smaller size, higher affinity, and better availability.  In additional to sTyr, we also evolved SH2 domain to recognize unphosphorylated substrate, which can potentially be used to turn on/off a signal in the absence of the required kinase activity.

Evolution of Src homology 2 domain

249th National Meeting (2015)

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