Figure 8. Summary schematic of novel CDKL5 substrates and functions in microtubule dynamics.

CDKL5 phosphorylates microtubule‐associated proteins EB2, MAP1S and ARHGEF2 at their RPXS motifs. Double phosphorylation of the MAP1S LC microtubule‐binding region decreases MAP1S affinity for microtubules. Loss of these MAP1S phosphorylations leads to impaired microtubule dynamic instability in CDKL5 KO neurons. Altered microtubule stability in CDKL5 KO neurons is also likely to be responsible for reduced cargo trafficking.