Allosteric Boost by TAB1 on the TAK1 Kinase Favorably Sculpts the Thermodynamic Landscape of Activation

The intricate mechanisms of allosteric regulation in
kinases are
of general interest to the scientific community for potential therapeutic
implications. However, the diversity among kinases and their regulatory
routes requires a case-by-case study to widen the repertoire of known
mechanisms. The present study achieves this by understanding TAK1
kinase activation by TAB1 as a model phenomenon for the first time.
Despite the known capacity of TAK1 to switch between its inactive
(“DFG-out”) and active-like (“DFG-in”)
conformations, the questionable role of TAB1 in offering an energetic
favor to this has been addressed here using sequential combination
of enhanced sampling methods like targeted molecular dynamics (TMD)
and Gaussian accelerated molecular dynamics (GaMD). It reveals how
a minimal domain of TAB1 sufficiently acts like a “catalytic
gear” by favorably sculpting TAK1’s thermodynamic landscape
(potential of mean force in 2D) that accelerates “in”–“out”
conformational switching of the conserved DFG motif. Standard molecular
dynamics simulations (∼5 μs) reveal that TAB1 fascinatingly
exploits the “lever-like” αF helix of TAK1 kinase
domain to remotely propel the DFG motif via subtle helical “unfolding–folding”
modifications within the kinase activation loop. The presence of two
charged residues on terminal poles of αF helix imparts it, with
this unique “lever-like” utility, and this turns out
to be one important signature of co-evolution between TAK1 and TAB1.
The entire mechanism of TAB1’s impact transduction, which is
found to be analogous to the moves in the popular “Chinese
checker” game, gives a clear proof of the “dynamics-driven
allostery” concept in kinases. The findings further benchmark
TAK1’s known autophosphorylation capacity. A novel insight
into kinase allostery is thus provided, which potentiates investigation
of similar capacities in other kinases.