6URQ

Complex structure of human poly-ADP-ribosyltransferase TNKS1 ARC2-ARC3 and P antigen family member 4 (PAGE4)

6URQ の概要

• エントリーDOI: 10.2210/pdb6urq/pdb
• 分子名称: Poly [ADP-ribose] polymerase tankyrase-1, P antigen family member 4, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: tnks, page4, tankyrase, parp, cancer-testis antigen, wnt signaling, transferase-transcription complex, transferase/transcription
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 92424.50

構造登録者

Zheng, Y.,Koirala, S.,Miller, D.,Potts, P.R. (登録日: 2019-10-24, 公開日: 2020-07-29, 最終更新日: 2023-10-11)

主引用文献

Koirala, S.,Klein, J.,Zheng, Y.,Glenn, N.O.,Eisemann, T.,Fon Tacer, K.,Miller, D.J.,Kulak, O.,Lu, M.,Finkelstein, D.B.,Neale, G.,Tillman, H.,Vogel, P.,Strand, D.W.,Lum, L.,Brautigam, C.A.,Pascal, J.M.,Clements, W.K.,Potts, P.R.
Tissue-Specific Regulation of the Wnt/ beta-Catenin Pathway by PAGE4 Inhibition of Tankyrase.
Cell Rep, 32:107922-107922, 2020

PubMed Abstract: Spatiotemporal control of Wnt/β-catenin signaling is critical for organism development and homeostasis. The poly-(ADP)-ribose polymerase Tankyrase (TNKS1) promotes Wnt/β-catenin signaling through PARylation-mediated degradation of AXIN1, a component of the β-catenin destruction complex. Although Wnt/β-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/β-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/β-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/β-catenin pathway.

PubMed: 32698014
DOI: 10.1016/j.celrep.2020.107922

実験手法

X-RAY DIFFRACTION (2.05 Å)