Journal
BIOPHYSICAL JOURNAL
Volume 120, Issue 16, Pages 3355-3362Publisher
CELL PRESS
DOI: 10.1016/j.bpj.2021.06.037
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Funding
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) Leading Initiative for Excellent Young Researchers
- Japan Society for the Promotion of Science (JSPS)/MEXT KAKENHI [JP21H00283, JP21H02418, JP19K16068, JP21K15084, JP18H05501]
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TAB2-binding protein 2 (TAB2) is known to bind K63-linked polyubiquitin chains via its C-terminal Npl4 zinc-finger (NZF) domain, but recent research reveals its interaction with K6-linked polyubiquitin chains as well. The crystal structure analysis shows that TAB2-NZF can interact with both distal and proximal ubiquitin moieties of K6-Ub2, similar to its interaction with K63-Ub2, except for the flexible C-terminal region of the distal ubiquitin. This study sheds light on the dual specificity of TAB2-NZF towards K6- and K63-linked ubiquitin chains.
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-angstrom 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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