Fig. 6: Proposed regulation model of hPhK activity.
From: Molecular basis for the regulation of human phosphorylase kinase by phosphorylation and Ca2+
a, b and c–g show the regulation of holoenzyme and protomer, respectively. In the inactive state, the active sites of the γ-CKD region are occupied by the γ-AID region. Inactive hPhK can be activated in two ways: phosphorylation/Ca2+ or pH 8.2/Ca2+. Phosphorylation primarily phosphorylates Ser27β, Ser701β, and Ser1018α, resulting in the four protomers moving towards the center, thus disrupting the stability of the γ-N lobe. Ca2+ binds to the δ subunit (CaM), causing the δ subunit to slide along the γ-CBD region, which disrupts the stability of the γ-C lobe. The two processes work together to allow the γ-CKD region to flip when the substrate GP approaches, thus exposing the catalytic sites. pH 8.2/Ca2+ can keep the γ-CKD region in a flexible state, with the catalytic site exposed. When the substrate approaches, it can directly exert catalytic activity. Phosphorylation sites are shown as purple balls, and Ca2+ are shown as green balls. Only important phosphorylation sites are shown for simplicity. The red lines represent the lock between the γ subunit and the other three subunits, while the black lines indicate no lock. Arrows in corresponding colors represent the vibration directions of the respective subunits or domains.
