Allosteric linkers in cAMP signalling.
Weak interactions mediated by dynamic linkers are key determinants of allosteric regulation in multidomain signalling proteins. However, the mechanisms of linker-dependent control have remained largely elusive. In the present article, we review an allosteric model introduced recently to explain how signalling proteins effectively sense and respond to weak interactions, such as those elicited by flexible linkers flanking globular domains. Central to this model is the idea that near degeneracy within the free energy landscape of conformational selection maximally amplifies the response to weak (~2RT), but conformation-selective interactions. The model was tested as proof of principle using the prototypical regulatory subunit (R) of protein kinase A and led to the unanticipated finding that dynamic linkers control kinase activation and inhibition by tuning the inhibitory pre-equilibrium of a minimally populated intermediate (apo R). A practical implication of the proposed model is a new strategy to design kinase inhibitors with enhanced potency through frustration-relieving mutations.
*Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada, L8S 4M1.
Madoka
M
Akimoto
*Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada, L8S 4M1.
Kody
K
Moleschi
†Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada, L8S 4M1.
Stephen
S
Boulton
*Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada, L8S 4M1.
Bryan
B
VanSchouwen
*Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada, L8S 4M1.
Rajeevan
R
Selvaratnam
Susan S
SS
Taylor
Giuseppe
G
Melacini
D000494:Allosteric Regulation; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015290:Second Messenger Systems; D013816:Thermodynamics
D047428:Protein Kinase Inhibitors; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases