title: Tankyrase Sterile α Motif Domain Polymerization Is Required for Its Role in Wnt Signaling.
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.
authors: Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec H3T 1J4, Canada.
authors: Amanda A
authors: AA
authors: Riccio
authors: Department of Biochemistry & Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors: Michael
authors: M
authors: McCauley
authors: Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec H3T 1J4, Canada.
authors: Marie-France
authors: MF
authors: Langelier
authors: Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec H3T 1J4, Canada. Electronic address: john.pascal@umontreal.ca.
authors: John M
authors: JM
authors: Pascal
mesh_terms: D060466:Axin Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D049109:Cell Proliferation; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D058105:Polymerization; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D054730:Protein Interaction Domains and Motifs; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000071682:Sterile Alpha Motif; D038501:Tankyrases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D060466:Axin Protein; D049452:Green Fluorescent Proteins; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D038501:Tankyrases; D051176:beta Catenin; C555451:AXIN1 protein, human; C495270:CTNNB1 protein, human; C418109:TNKS protein, human
keywords: Wnt/β-catenin signaling; X-ray crystallography; poly(ADP-ribose) polymerase; tankyrase