Redefining PTB domain into independently functional dual cores

Current understanding of phosphotyrosine binding (PTB) domain is limited. Recently, we revealed a novel atypical phosphotyrosine binding (aPTB) domain in CCM2, making it a dual PTB domain-containing protein. Since aPTB domain is only 1/3 of the size of typical PTB domain, we explored the possibility to decrease the size of PTB domain and demonstrate that the typical PTB domain can be divided into two similarly structural and functional cores that can independently bind to NPXY motif. Further, we reduced each PTB core into a minimum core motif (mCore) which is the functional unit of PTB domains and structurally similar to the novel aPTB domain. Based on structural data, we developed several cis- and trans-inhibitors for NPXY binding scheme, with potential applications for therapeutic strategies in human health conditions.