Background: Glycogen phosphorylases (GPs) catalyze the conversion of t
he storage form of carbohydrate (glycogen) to the readily usable form
(glucose-1-phosphate) to provide cellular energy. Members of this enzy
me family have evolved diverse regulatory mechanisms that control a co
nserved catalytic function. The mammalian and yeast GPs are expressed
as inactive forms requiring phosphorylation for activation. Phosphoryl
ation of yeast GP occurs at a distinct site from that of mammalian GP.
This work addresses the structural basis by which distinct activation
signals relay to the conserved catalytic site in yeast and mammalian
GPs. Such knowledge may help understand the principles by which divers
e biological regulation evolves. Results: We have compared the crystal
structures of the unphosphorylated and phosphorylated forms of yeast
GP and propose a relay which links phosphorylation to enzyme activatio
n. Structural components along the activation relay becomes more conse
rved within the GP family downstream along the relay, towards the cata
lytic center. Despite distinct upstream activation signals, a response
element downstream of the relay leading to the catalytic center is co
nserved in all GPs. The response element consists of ten hydrophobic r
esidues dispersed over two subunits of the homodimer. Phosphorylation
induces hydrophobic condensation of these residues via structural rear
rangement, which triggers conformation change of the active site GATE
loop, leading to enzyme activation. Conclusions: Members of the GP fam
ily with diverse activation mechanisms have evolved from a constitutiv
ely active ancestral enzyme which has the TOWER hydrophobic response e
lement in the active position. Diverse regulation evolved as a result
of evolutionary constraint on the downstream response element in the a
ctive state, coupled with flexibility and variability in elements of t
he upstream relays.