Redefining PTB domain into independently functional dual cores

• Published in: Biochemical and biophysical research communications 2020-04, Vol.524 (3), p.595-607
• Main Authors: Zhang, Jun, Padarti, Akhil, Jiang, Xiaoting, Abou-Fadel, Johnathan
• Format: Article
• Language: English
• Subjects: Minimal PTB core motif; NPXY motifs; Phosphotyrosine binding domain (PTB) and atypical PTB (aPTB) domains; PTB core
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2020.01.114

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. •The typical PTB domain can be divided into two similar structural and functional cores that can each bind to NPXY motif.•Each PTB core can be further reduced to a minimum core motif (mCore) as the basic functional unit of the PTB domain.•Several cis- and trans-inhibitors for NPXY binding scheme were developed, which have great potential therapeutic applications.