The pseudokinase domains of guanylyl cyclase–A and –B allosterically increase the affinity of their catalytic domains for substrate

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Science Signaling  29 Jan 2019:
Vol. 12, Issue 566, eaau5378
DOI: 10.1126/scisignal.aau5378

Allosteric regulation through pseudokinase domains

Pseudokinase domains are similar to kinase domains, but they lack catalytic activity. Although many domains originally classified as pseudokinases were subsequently shown to have limited or context-dependent kinase activity, some act as scaffolds or allosteric regulators. The natriuretic peptide receptors GC-A and GC-B contain both pseudokinase and guanylyl cyclase domains. By combining homology modeling with biochemical analysis of mutant proteins, Edmund et al. found that the pseudokinase domains of GC-A and GC-B were allosteric regulators of the guanylyl cyclase domains. ATP bound to and stabilized the pseudokinase domain similarly to its stabilization of the active conformation of the prototypical kinase PKA. This, in turn, stimulated the receptors’ guanylyl cyclase activities. Thus, the pseudokinase domains of GC-A and GC-B promote the catalytic activity of these receptors through an allosteric mechanism that is conserved with catalytically active kinases.

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