期刊
CELL
卷 147, 期 6, 页码 1340-1354出版社
CELL PRESS
DOI: 10.1016/j.cell.2011.10.046
关键词
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资金
- National Center for Research Resources at the National Institutes of Health [RR-15301]
- U.S. DOE [DE-AC02-06CH11357]
- Human Frontier Science Program (HFSP)
- European Molecular Biology Organization (EMBO)
- Canadian Institutes of Health Research [MOP-36399, MOP-6849]
- Ontario Research Fund [GL2-01-025]
- Terry Fox Program [20003]
- Canada Research Chair in Structural Biology
The poly(ADP-ribose)polymerases Tankyrase 1/2 (TNKS/TNKS2) catalyze the covalent linkage of ADP-ribose polymer chains onto target proteins, regulating their ubiquitylation, stability, and function. Dysregulation of substrate recognition by Tankyrases underlies the human disease cherubism. Tankyrases recruit specific motifs (often called RxxPDG hexapeptides) in their substrates via an N-terminal region of ankyrin repeats. These ankyrin repeats form five domains termed ankyrin repeat clusters (ARCs), each predicted to bind substrate. Here we report crystal structures of a representative ARC of TNKS2 bound to targeting peptides from six substrates. Using a solution-based peptide library screen, we derive a rule-based consensus for Tankyrase substrates common to four functionally conserved ARCs. This 8-residue consensus allows us to rationalize all known Tankyrase substrates and explains the basis for cherubism-causing mutations in the Tankyrase substrate 3BP2. Structural and sequence information allows us to also predict and validate other Tankyrase targets, including Disc1, Striatin, Fat4, RAD54, BCR, and MERIT40.
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