TAK1-binding protein 2 (TAB2) has generally been considered to bind specifically to K63-linked polyubiquitin chains via its C-terminal Npl4 zinc-finger (NZF) domain. However, a recent study showed that the NZF domain of TAB2 (TAB2-NZF) could also interact with K6-linked polyubiquitin chains. Here, we report the crystal structure of TAB2-NZF in complex with K6-linked diubiquitin (K6-Ub2) at 1.99-Å resolution. TAB2-NZF simultaneously interacts with the distal and proximal ubiquitin moieties of K6-Ub2. By comparing the structures of TAB2-NZF in complex with K6-Ub2 and with K63-linked diubiquitin (K63-Ub2), we reveal that the binding mechanism of TAB2-NZF with K6-Ub2 is similar to that with K63-Ub2, except for the flexible C-terminal region of the distal ubiquitin. Therefore, we conclude that the C-terminal flexibility of the distal ubiquitin contributes to the dual specificity of TAB2-NZF toward K6- and K63-linked ubiquitin chains. This study provides important insights into the functions of K6-linked ubiquitin chains, which are currently unclear.
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