Ancient origins of allosteric activation in a Ser-Thr kinase

A myriad of cellular events are regulated by allostery; therefore, evolution of this process is of fundamental interest. Here, we use ancestral sequence reconstruction to resurrect ancestors of two colocalizing proteins, Aurora A kinase and its allosteric activator TPX2 (targeting protein for Xklp2)...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2020-02, Vol.367 (6480)
Main Authors: Hadzipasic, Adelajda, Wilson, Christopher, Nguyen, Vy, Kern, Nadja, Kim, Chansik, Pitsawong, Warintra, Villali, Janice, Zheng, Yuejiao, Kern, Dorothee
Format: Article
Language:English
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Science & Technology - Other Topics
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Summary:A myriad of cellular events are regulated by allostery; therefore, evolution of this process is of fundamental interest. Here, we use ancestral sequence reconstruction to resurrect ancestors of two colocalizing proteins, Aurora A kinase and its allosteric activator TPX2 (targeting protein for Xklp2), to experimentally characterize the evolutionary path of allosteric activation. Autophosphorylation of the activation loop is the most ancient activation mechanism; it is fully developed in the oldest kinase ancestor and has remained stable over 1 billion years of evolution. As the microtubule-associated protein TPX2 appeared, efficient kinase binding to TPX2 evolved, likely owing to increased fitness by virtue of colocalization. Subsequently, TPX2-mediated allosteric kinase regulation gradually evolved. Surprisingly, evolution of this regulation is encoded in the kinase and did not arise by a dominating mechanism of coevolution.
ISSN:0036-8075
1095-9203