7e62
Mouse TAB2 NZF in complex with Lys6-linked diubiquitin
Structural highlights
FunctionRS27A_MOUSE Ubiquitin: Exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.[1] 40S Ribosomal protein S27a: Component of the 40S subunit of the ribosome.[2] Publication Abstract from PubMedTAK1-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-Ub(2)) at 1.99-A resolution. TAB2-NZF simultaneously interacts with the distal and proximal ubiquitin moieties of K6-Ub(2). By comparing the structures of TAB2-NZF in complex with K6-Ub(2) and with K63-linked diubiquitin (K63-Ub(2)), we reveal that the binding mechanism of TAB2-NZF with K6-Ub(2) is similar to that with K63-Ub(2), 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. Structural basis for specific recognition of K6-linked polyubiquitin chains by the TAB2 NZF domain.,Li Y, Okatsu K, Fukai S, Sato Y Biophys J. 2021 Aug 17;120(16):3355-3362. doi: 10.1016/j.bpj.2021.06.037. Epub , 2021 Jul 7. PMID:34242591[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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