Tankyrase-1 (TNKS1/PARP-5a) is a poly(ADP-ribose) polymerase (PARP) enzyme that
regulates multiple cellular processes creating a poly(ADP-ribose)
posttranslational modification that can lead to target protein turnover. TNKS1
thereby controls protein levels of key components of signaling pathways,
including Axin1, the limiting component of the destruction complex in canonical
Wnt signaling that degrades β-catenin to prevent its coactivator function in
gene expression. There are limited molecular level insights into TNKS1
regulation in cell signaling pathways. TNKS1 has a sterile α motif (SAM) domain
that is known to mediate polymerization, but the functional requirement for SAM
polymerization has not been assessed. We have determined the crystal structure
of wild-type human TNKS1 SAM domain and used structure-based mutagenesis to
disrupt polymer formation and assess the consequences on TNKS1 regulation of
β-catenin-dependent transcription. Our data indicate the SAM polymer is
critical for TNKS1 catalytic activity and allows TNKS1 to efficiently access
cytoplasmic signaling complexes.
