Allosteric linkers in cAMP signalling

Madoka Akimoto, Kody Moleschi, Stephen Boulton, Bryan VanSchouwen, Rajeevan Selvaratnam, Susan S. Taylor, Giuseppe Melacini

研究成果: Article査読

16 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)139-144
ページ数6
ジャーナルBiochemical Society Transactions
42
1
DOI
出版ステータスPublished - 2014 2月

ASJC Scopus subject areas

  • 生化学

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