Lehtiö Lari, Collins Ruairi, van den Berg Susanne, Johansson Andreas, Dahlgren Lars-Göran, Hammarström Martin, Helleday Thomas, Holmberg-Schiavone Lovisa, Karlberg Tobias, Weigelt Johan
Structural Genomics Consortium, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm, Sweden.
J Mol Biol. 2008 May 23;379(1):136-45. doi: 10.1016/j.jmb.2008.03.058. Epub 2008 Apr 3.
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.
端锚聚合酶是最近发现的蛋白质，参与细胞中的许多重要功能，包括端粒稳态和有丝分裂。端锚聚合酶通过聚（ADP-核糖）基化调节靶蛋白的活性，在此我们报道了人端锚聚合酶1催化性聚（ADP-核糖）聚合酶（PARP）结构域的结构。这是端锚聚合酶亚家族PARP结构域的首个结构。目前的结构表明，端锚聚合酶含有一个未被预测到的短锌结合基序。端锚聚合酶活性有助于在各种癌细胞中观察到的端粒延长，并且端锚聚合酶抑制已被认为是癌症治疗的潜在途径。与其他PARP相比，在端锚聚合酶1底物结合位点的内衬区域观察到显著的结构差异。这些发现对于促进基于结构的选择性PARP抑制剂，特别是端锚聚合酶抑制剂的设计具有重要价值。
