4 cAMP,

4 cAMP,

Regulatory subunits: autoinhibitory domains buried

Active PKA

Catalytic subunits: open substrate-binding sites

FIGURE 12-15 Activation of cAMP-dependent protein kinase, PKA.

(a) A schematic representation of the inactive R2C2 tetramer, in which the autoinhibitory domain of a regulatory (R) subunit occupies the substrate-binding site, inhibiting the activity of the catalytic (C) subunit. Cyclic AMP activates PKA by causing dissociation of the C sub-units from the inhibitory R subunits. Activated PKA can phosphorylate a variety of protein substrates (Table 12-3) that contain the PKA consensus sequence (X-Arg-(Arg/Lys)-X-(Ser/Thr)-B, where X is any

One downstream effect of epinephrine is to activate glycogen phosphorylase b. This conversion is promoted by the enzyme phosphorylase b kinase, which catalyzes the phosphorylation of two specific Ser residues in phosphorylase b, converting it to phosphorylase a (see Fig. 6-31). Cyclic AMP does not affect phosphorylase b kinase directly. Rather, cAMP-dependent protein kinase, also called protein kinase A or PKA, which is allosterically activated by cAMP (Fig. 12-12, step ©), catalyzes the phosphorylation of inactive phosphorylase b kinase to yield the active form.

The inactive form of PKA contains two catalytic sub-units (C) and two regulatory subunits (R) (Fig. 12-15a), which are similar in sequence to the catalytic and regulatory domains of PKG (cGMP-dependent protein kinase). The tetrameric R2C2 complex is catalytically inactive, because an autoinhibitory domain of each R subunit occupies the substrate-binding site of each C subunit. When cAMP binds to two sites on each R subunit, the R subunits undergo a conformational change and the R2C2 complex dissociates to yield two free, residue and B is any hydrophobic residue), including phosphorylase b kinase. (b) The substrate-binding region of a catalytic subunit revealed by x-ray crystallography (derived from PDB ID 1JBP). Enzyme side chains known to be critical in substrate binding and specificity are in blue. The peptide substrate (red) lies in a groove in the enzyme surface, with its Ser residue (yellow) positioned in the catalytic site. In the inactive R2C2 tetramer, the autoinhibitory domain of R lies in this groove, blocking access to the substrate.

catalytically active C subunits. This same basic mechanism—displacement of an autoinhibitory domain— mediates the allosteric activation of many types of protein kinases by their second messengers (as in Figs 12-7 and 12-23, for example).

As indicated in Figure 12-12 (step ©), PKA regulates a number of enzymes (Table 12-3). Although the proteins regulated by cAMP-dependent phosphorylation have diverse functions, they share a region of sequence similarity around the Ser or Thr residue that undergoes phosphorylation, a sequence that marks them for regulation by PKA. The catalytic site of PKA (Fig. 12-15b) interacts with several residues near the Thr or Ser residue in the target protein, and these interactions define the substrate specificity. Comparison of the sequences of a number of protein substrates for PKA has yielded the consensus sequence—the specific neighboring residues needed to mark a Ser or Thr residue for phosphorylation (see Table 12-3).

Signal transduction by adenylyl cyclase entails several steps that amplify the original hormone signal (Fig.

Epinephrine x molecules

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