This is the first unpublished report of direct role of Ca-ATPase (PMCA) in Ca-signaling to hold homeostasis. Based on our published reports (during 80’s) on allosteric regulation of the Na-pump by the ubiquitous NaAF (of 170 k Da mass) we found new molecular insights into the Ca-signaling event during homeostasis. The dominating 50-year old single-topology Post-Albers scheme fails to accommodate these findings.
Briefly, the entropy-driven NaAF-regulated process involves energization of the dual-topology (mirror-image orientation of 2α-subunits) P2-ATPase molecule binding ATP to form the transition-state (E*.ATP) complex, with simultaneous ligation of cytosolic high-affinity Na and trans-bilayer K (an allosteric creation) with simultaneous conformation shift of embedded ion-channels. This causes instant hydrolysis of ATP from E*.ATP complex with the movement of Na and K across by bringing the enzyme back to original E-state (backward shift) to start a new cycle. The Na and K channels across are regulated by low-affinity K site at each unloading end. Entire process is under allosteric control of local Ca (< 0.1 to > 10 µM); low Ca stimulates and high Ca inhibits the Na-pump turning it into a temporary Ca-ATPase pump to remove excess Ca, then continuing Na-pump function with a rhythmic stop-and-go style dancing.
The entire homeostasis scenario is visualized as an allosteric all-time dance of the P2-ATPase system in close embrace with the endogenous activator protein with cheering support from the cytosolic neighborhood Ca. From the exclusive functionality of the P2-ATPase system, it appears that the ancestral monomeric protein are assembled into plasma membrane as symmetric (mirror-image form) as well as iso-energetic (open-to both inside and outside) becoming the ideal vehicle for bidirectional ion-transport.
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