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Title: Ancient origins of allosteric activation in a Ser-Thr kinase

Abstract

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.

Authors:
ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [1];  [1];  [1];  [1]; ORCiD logo [1]
  1. Department of Biochemistry, Brandeis University, Waltham, MA 02454, USA., Howard Hughes Medical Institute, Brandeis University, Waltham, MA 02454, USA.
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1600873
Grant/Contract Number:  
[FG02-05ER15699]
Resource Type:
Published Article
Journal Name:
Science
Additional Journal Information:
[Journal Name: Science Journal Volume: 367 Journal Issue: 6480]; Journal ID: ISSN 0036-8075
Publisher:
American Association for the Advancement of Science (AAAS)
Country of Publication:
United States
Language:
English

Citation Formats

Hadzipasic, Adelajda, Wilson, Christopher, Nguyen, Vy, Kern, Nadja, Kim, Chansik, Pitsawong, Warintra, Villali, Janice, Zheng, Yuejiao, and Kern, Dorothee. Ancient origins of allosteric activation in a Ser-Thr kinase. United States: N. p., 2020. Web. doi:10.1126/science.aay9959.
Hadzipasic, Adelajda, Wilson, Christopher, Nguyen, Vy, Kern, Nadja, Kim, Chansik, Pitsawong, Warintra, Villali, Janice, Zheng, Yuejiao, & Kern, Dorothee. Ancient origins of allosteric activation in a Ser-Thr kinase. United States. doi:10.1126/science.aay9959.
Hadzipasic, Adelajda, Wilson, Christopher, Nguyen, Vy, Kern, Nadja, Kim, Chansik, Pitsawong, Warintra, Villali, Janice, Zheng, Yuejiao, and Kern, Dorothee. Thu . "Ancient origins of allosteric activation in a Ser-Thr kinase". United States. doi:10.1126/science.aay9959.
@article{osti_1600873,
title = {Ancient origins of allosteric activation in a Ser-Thr kinase},
author = {Hadzipasic, Adelajda and Wilson, Christopher and Nguyen, Vy and Kern, Nadja and Kim, Chansik and Pitsawong, Warintra and Villali, Janice and Zheng, Yuejiao and Kern, Dorothee},
abstractNote = {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.},
doi = {10.1126/science.aay9959},
journal = {Science},
number = [6480],
volume = [367],
place = {United States},
year = {2020},
month = {2}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1126/science.aay9959

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