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Structure. 2016 Sep 6;24(9):1573-81. doi: 10.1016/j.str.2016.06.022. Epub 2016 Aug 4.

Tankyrase Sterile α Motif Domain Polymerization Is Required for Its Role in Wnt Signaling.

Author information

1
Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec H3T 1J4, Canada.
2
Department of Biochemistry & Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
3
Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec H3T 1J4, Canada. Electronic address: john.pascal@umontreal.ca.

Abstract

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.

KEYWORDS:

Wnt/β-catenin signaling; X-ray crystallography; poly(ADP-ribose) polymerase; tankyrase

PMID:
27499439
PMCID:
PMC5109827
DOI:
10.1016/j.str.2016.06.022
[Indexed for MEDLINE]
Free PMC Article

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