TBM Hunter: Identify and Score Canonical, Extended, and Unconventional Tankyrase-Binding Motifs in Any Protein

Abstract

Tankyrases, a versatile protein group within the poly(ADP-ribose) polymerase family, are essential for post-translational poly(ADP-ribosyl)ation, influencing various cellular functions and contributing to diseases, particularly cancer. Consequently, tankyrases have become important targets for anti-cancer drug development. Emerging approaches in drug discovery aim to disrupt interactions between tankyrases and their binding partners, which hinge on tankyrase-binding motifs (TBMs) within partner proteins and ankyrin repeat cluster domains within tankyrases. Our study addresses the challenge of identifying and ranking TBMs. We have conducted a comprehensive review of the existing literature, classifying TBMs into three distinct groups, each with its own scoring system. To facilitate this process, we introduce TBM Hunter-an accessible, web-based tool. This user-friendly platform provides a cost-free and efficient means to screen and assess potential TBMs within any given protein. TBM Hunter can handle individual proteins or lists of proteins simultaneously. Notably, our results demonstrate that TBM Hunter not only identifies known TBMs but also uncovers novel ones. In summary, our study offers an all-encompassing perspective on TBMs and presents an easy-to-use, precise, and free tool for identifying and evaluating potential TBMs in any protein, thereby enhancing research and drug development efforts focused on tankyrases.

Keywords: PARsylation; RNF146; SASH1; anti-cancer drug; poly(ADP-ribose) polymerase (PARP); poly(ADP-ribosyl)ation (PARylation); tankyrase (TNKS); tankyrase 2 (TNKS2); tankyrase-binding motif (TBM).

Figure 1

Tankyrases are multifunctional proteins with scaffolding capacity on the N-terminal and an enzymatic PARP domain at the C-terminal.

Figure 2

Homepage of the TBM Search Project (TBM Hunter) at https://shellmanlab.github.io/. The webpage is divided into two sections: the left side is the input and output areas for the two function buttons, “Find and Score motifs!” and “Score any 8-amino-acid sequence”. The right side provides the relevant information and references. Both buttons operate independently, with their results displayed at the bottom of the webpage.