Two-sided ubiquitin binding explains specificity of the TAB2 NZF domain

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.

[1]  Scott D Emr,et al.  Ubiquitin interactions of NZF zinc fingers , 2004, The EMBO journal.

[2]  D. Fushman,et al.  Avid interactions underlie the K63-linked polyubiquitin binding specificities observed for UBA domains , 2009, Nature Structural &Molecular Biology.

[3]  Soichi Wakatsuki,et al.  Ubiquitin-binding domains — from structures to functions , 2009, Nature Reviews Molecular Cell Biology.

[4]  P. Cohen,et al.  Interleukin-1 (IL-1) Induces the Lys63-Linked Polyubiquitination of IL-1 Receptor-Associated Kinase 1 To Facilitate NEMO Binding and the Activation of IκBα Kinase , 2008, Molecular and Cellular Biology.

[5]  Michael Assfalg,et al.  Structural determinants for selective recognition of a Lys48-linked polyubiquitin chain by a UBA domain. , 2005, Molecular cell.

[6]  David Komander,et al.  Molecular discrimination of structurally equivalent Lys 63‐linked and linear polyubiquitin chains , 2009, EMBO reports.

[7]  Zhijian J. Chen,et al.  The role of ubiquitin in NF-kappaB regulatory pathways. , 2009, Annual review of biochemistry.

[8]  Kazuhiro Iwai,et al.  Linear polyubiquitination: a new regulator of NF‐κB activation , 2009, EMBO reports.

[9]  Yusuke Sato,et al.  Crystal structure of the NEMO ubiquitin‐binding domain in complex with Lys 63‐linked di‐ubiquitin , 2009, FEBS letters.

[10]  Su-Chang Lin,et al.  TAK1-dependent Signaling Requires Functional Interaction with TAB2/TAB3* , 2006, Journal of Biological Chemistry.

[11]  Hao Wu,et al.  Structural basis for recognition of diubiquitins by NEMO. , 2009, Molecular cell.

[12]  D. Komander.  The emerging complexity of protein ubiquitination. , 2009, Biochemical Society transactions.

[13]  Nobuhiro Suzuki,et al.  Specific Recognition of Linear Ubiquitin Chains by NEMO Is Important for NF-κB Activation , 2009, Cell.

[14]  Zhijian J. Chen,et al.  TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains. , 2004, Molecular cell.

[15]  Zhijian J. Chen,et al.  Nonproteolytic functions of ubiquitin in cell signaling. , 2009, Molecular cell.

[16]  Zhijian J. Chen,et al.  Direct Activation of Protein Kinases by Unanchored Polyubiquitin Chains , 2009, Nature.