Human genome‐wide analysis and identification of the hyperphosphorylation‐elicited interactions between subarachnoid tau protein and phosphoprotein‐binding domains.

Abnormally hyperphosphorylated tau can be recognized by a variety of phosphoprotein‐binding domains (PBDs) to elicit downstream tau signaling in neuropathology, which has been found to have a potential association with subarachnoid hemorrhage. In this study, the genome‐wide binding behavior of tau phosphorylation sites (p‐sites) to PBDs involved in subarachnoid hyperphosphorylation events was systematically profiled at molecular level by integrating peptide docking, structural minimization, affinity scoring, and binding assay, from which a number of potent PBD–p‐site interaction pairs were identified. It was revealed that the PBD domains exhibit distinct binding preferences for phosphotyrosine, phosphoserine, and phosphothreonine p‐sites; the PBD‐recognition specificity of different tau p‐sites is not overlapped with each other, and their phosphorylations would therefore regulate varying biological functions in tau signaling. A number of PBD–p‐site pairs were identified to have potent binding potency as compared to others. The KCIP–pS[393–399] pair was found as a strong binder, which was further optimized with a rational peptide design protocol to derive a number of affinity‐improved phosphopeptides. Structural analysis revealed diverse noncovalent chemical forces across the complex interface of KCIP domain with a designed high‐affinity pS[393–399]‐d4, which confers both stability and specificity to the domain–peptide complex system, with affinity improved by 10.9‐fold relative to the native pS[393–399]. [ABSTRACT FROM AUTHOR]