Deep evolutionary conservation of an intramolecular protein kinase activation mechanism

Hong, W., Han, J., Miranda-Saavedra, D., Luebbering, N., Singh, A., Sibbet, G., Ferguson, M.A.J. and Cleghon, V. (2012) Deep evolutionary conservation of an intramolecular protein kinase activation mechanism. PLoS ONE, 7(1), e29702. (doi: 10.1371/journal.pone.0029702) (PMID:22235329) (PMCID:PMC3250476)

Abstract

DYRK-family kinases employ an intramolecular mechanism to autophosphorylate a critical tyrosine residue in the activation loop. Once phosphorylated, DYRKs lose tyrosine kinase activity and function as serine/threonine kinases. DYRKs have been characterized in organisms from yeast to human; however, all entities belong to the Unikont supergroup, only one of five eukaryotic supergroups. To assess the evolutionary age and conservation of the DYRK intramolecular kinase-activation mechanism, we surveyed 21 genomes representing four of the five eukaryotic supergroups for the presence of DYRKs. We also analyzed the activation mechanism of the sole DYRK (class 2 DYRK) present in Trypanosoma brucei (TbDYRK2), a member of the excavate supergroup and separated from Drosophila by ~850 million years. Bioinformatics showed the DYRKs clustering into five known subfamilies, class 1, class 2, Yaks, HIPKs and Prp4s. Only class 2 DYRKs were present in all four supergroups. These diverse class 2 DYRKs also exhibited conservation of N-terminal NAPA regions located outside of the kinase domain, and were shown to have an essential role in activation loop autophosphorylation of Drosophila DmDYRK2. Class 2 TbDYRK2 required the activation loop tyrosine conserved in other DYRKs, the NAPA regions were critical for this autophosphorylation event, and the NAPA-regions of Trypanosoma and human DYRK2 complemented autophosphorylation by the kinase domain of DmDYRK2 in trans. Finally, sequential deletion analysis was used to further define the minimal region required for trans-complementation. Our analysis provides strong evidence that class 2 DYRKs were present in the primordial or root eukaryote, and suggest this subgroup may be the oldest, founding member of the DYRK family. The conservation of activation loop autophosphorylation demonstrates that kinase self-activation mechanisms are also primitive.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Singh, Mr Aman and Cleghon, Dr Vaughan and Sibbet, Dr Gary
• Authors: Hong, W., Han, J., Miranda-Saavedra, D., Luebbering, N., Singh, A., Sibbet, G., Ferguson, M.A.J., and Cleghon, V.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: PLoS ONE
• Publisher: Public Library of Science
• ISSN: 1932-6203
• ISSN (Online): 1932-6203
• Copyright Holders: Copyright © 2012 The Authors
• First Published: First published in PLoS ONE 2012 7(1): e29702
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher