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Thymidine kinase 1 regulatory fine-tuning through tetramer formation

Journal article
Authors Z. Mutahir
Anders R Clausen
K. M. Andersson
S. M. Wisen
B. Munch-Petersen
J. Piskur
Published in Febs j
Volume 280
Issue 6
Pages 1531-41
ISSN 1742-464x
Publication year 2013
Published at
Pages 1531-41
Language en
Links dx.doi.org/10.1111/febs.12154
Keywords Adenosine Triphosphate/chemistry, Amino Acid Sequence, Animals, Arabidopsis/enzymology/genetics, Bacillus cereus/enzymology/genetics, Bacterial Proteins/chemistry/genetics, Caenorhabditis elegans/enzymology/genetics, Chromatography, Gel, Cloning, Molecular, Dictyostelium/enzymology/genetics, Enzyme Assays, Evolution, Molecular, Genetic Vectors/chemistry/genetics, Humans, Open Reading Frames, Phylogeny, Plant Proteins/chemistry/genetics, Protein Folding, *Protein Multimerization, Protein Structure, Secondary, Protozoan Proteins/chemistry/genetics, Recombinant Proteins/chemistry/genetics, Thymidine Kinase/*chemistry/genetics
Subject categories Biochemistry and Molecular Biology

Abstract

Thymidine kinase 1 (TK1) provides a crucial precursor, deoxythymidine monophosphate, for nucleic acid synthesis, and the activity of TK1 increases by up to 200-fold during the S-phase of cell division in humans. An important part of the regulatory checkpoints is the ATP and enzyme concentration-dependent transition of TK1 from a dimer with low catalytic efficiency to a tetramer with high catalytic efficiency. This regulatory fine-tuning serves as an additional control to provide a balanced pool of nucleic acid precursors in the cell. We subcloned and over-expressed 10 different TK1s, originating from widely different organisms, and characterized their kinetic and oligomerization properties. Whilst bacteria, plants and Dictyostelium only exhibited dimeric TK1, we found that all animals had a tetrameric TK1. However, a clear ATP-dependent switch between dimer and tetramer was found only in higher vertebrates and was especially pronounced in mammalian and bird TK1s. We suggest that the dimer form is the original form and that the tetramer originated in the animal lineage after the split of Dictyostelium and the lineages leading to invertebrates and vertebrates. The efficient switching mechanism was probably first established in warm-blooded animals when they separated from the rest of the vertebrates.

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