6urq
Complex structure of human poly-ADP-ribosyltransferase TNKS1 ARC2-ARC3 and P antigen family member 4 (PAGE4)
Structural highlights
FunctionTNKS1_HUMAN Poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking. Acts as an activator of the Wnt signaling pathway by mediating poly-ADP-ribosylation (PARsylation) of AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex: poly-ADP-ribosylated target proteins are recognized by RNF146, which mediates their ubiquitination and subsequent degradation. Also mediates PARsylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates PARsylation of TERF1, thereby contributing to the regulation of telomere length. Involved in centrosome maturation during prometaphase by mediating PARsylation of HEPACAM2/MIKI. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles. May be involved in spindle pole assembly through PARsylation of NUMA1.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedSpatiotemporal control of Wnt/beta-catenin signaling is critical for organism development and homeostasis. The poly-(ADP)-ribose polymerase Tankyrase (TNKS1) promotes Wnt/beta-catenin signaling through PARylation-mediated degradation of AXIN1, a component of the beta-catenin destruction complex. Although Wnt/beta-catenin is a niche-restricted signaling program, tissue-specific factors that regulate TNKS1 are not known. Here, we report prostate-associated gene 4 (PAGE4) as a tissue-specific TNKS1 inhibitor that robustly represses canonical Wnt/beta-catenin signaling in human cells, zebrafish, and mice. Structural and biochemical studies reveal that PAGE4 acts as an optimal substrate decoy that potently hijacks substrate binding sites on TNKS1 to prevent AXIN1 PARylation and degradation. Consistently, transgenic expression of PAGE4 in mice phenocopies TNKS1 knockout. Physiologically, PAGE4 is selectively expressed in stromal prostate fibroblasts and functions to establish a proper Wnt/beta-catenin signaling niche through suppression of autocrine signaling. Our findings reveal a non-canonical mechanism for TNKS1 inhibition that functions to establish tissue-specific control of the Wnt/beta-catenin pathway. Tissue-Specific Regulation of the Wnt/beta-Catenin Pathway by PAGE4 Inhibition of Tankyrase.,Koirala S, Klein J, Zheng Y, Glenn NO, Eisemann T, Fon Tacer K, Miller DJ, Kulak O, Lu M, Finkelstein DB, Neale G, Tillman H, Vogel P, Strand DW, Lum L, Brautigam CA, Pascal JM, Clements WK, Potts PR Cell Rep. 2020 Jul 21;32(3):107922. doi: 10.1016/j.celrep.2020.107922. PMID:32698014[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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