The protein kinase TAK1 is activated by binding to Lys63 (K63)-linked ubiquitin chains through its subunit TAB2. Here we analyze crystal structures of the TAB2 NZF domain bound to Lys63-linked di- and triubiquitin, revealing that TAB2 binds adjacent ubiquitin moieties via two distinct binding sites. The conformational constraints imposed by TAB2 on a Lys63 dimer cannot be adopted by linear chains, explaining why TAK1 cannot be activated by linear ubiquitination events.
Kulathu, Y., Akutsu, M., Bremm, A., Hofmann, K., & Komander, D. (2009). Two-sided ubiquitin binding explains specificity of the TAB2 NZF domain. Nature Structural & Molecular Biology, 16(12), 1328-30. https://doi.org/10.1038/nsmb.1731