Zinc binding catalytic domain of human tankyrase 1 |
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Authors: | Lehtiö Lari Collins Ruairi van den Berg Susanne Johansson Andreas Dahlgren Lars-Göran Hammarström Martin Helleday Thomas Holmberg-Schiavone Lovisa Karlberg Tobias Weigelt Johan |
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Institution: | 1 Structural Genomics Consortium, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm, Sweden 2 Department of Genetics, Microbiology and Toxicology, Stockholm University, S-106 91 Stockholm, Sweden 3 Radiation Oncology and Biology, University of Oxford, Oxford OX3 7LJ, UK |
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Abstract: | Tankyrases are recently discovered proteins implicated in many important functions in the cell including telomere homeostasis and mitosis. Tankyrase modulates the activity of target proteins through poly(ADP-ribosyl)ation, and here we report the structure of the catalytic poly(ADP-ribose) polymerase (PARP) domain of human tankyrase 1. This is the first structure of a PARP domain from the tankyrase subfamily. The present structure reveals that tankyrases contain a short zinc-binding motif, which has not been predicted. Tankyrase activity contributes to telomere elongation observed in various cancer cells and tankyrase inhibition has been suggested as a potential route for cancer therapy. In comparison with other PARPs, significant structural differences are observed in the regions lining the substrate-binding site of tankyrase 1. These findings will be of great value to facilitate structure-based design of selective PARP inhibitors, in general, and tankyrase inhibitors, in particular. |
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Keywords: | TNKS tankyrase TRF1 telomeric repeat binding factor PARP poly(ADP-ribose) polymerase PAR poly(ADP-ribose) PARsylation poly(ADP-ribos)ylation NI nicotinamide AD adenosine TCEP tris(2-carboxyethyl)phosphine |
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