2wx1

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TAB2 NZF DOMAIN IN COMPLEX WITH Lys63-linked tri-ubiquitin, P212121

Structural highlights

2wx1 is a 3 chain structure with sequence from Bos taurus and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3Å
Ligands:ZN
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TAB2_HUMAN Defects in TAB2 are the cause of congenital heart disease non-syndromic type 2 (CHTD2) [MIM:612863. It is a disease characterized by congenital developmental abnormalities involving structures of the heart. Clinical features include left ventricular outflow tract obstruction, subaortic stenosis, residual aortic regurgitation, atrial fibrillation, bicuspid aortic valve and aortic dilation. Note=A chromosomal aberration involving TAB2 has been found in a family with congenital heart disease. Translocation t(2;6)(q21;q25).[1]

Function

TAB2_HUMAN Adapter linking MAP3K7/TAK1 and TRAF6. Promotes MAP3K7 activation in the IL1 signaling pathway. The binding of 'Lys-63'-linked polyubiquitin chains to TAB2 promotes autophosphorylation of MAP3K7 at 'Thr-187'. Involved in heart development.[2] [3] [4]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

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.

Two-sided ubiquitin binding explains specificity of the TAB2 NZF domain.,Kulathu Y, Akutsu M, Bremm A, Hofmann K, Komander D Nat Struct Mol Biol. 2009 Dec;16(12):1328-30. Epub 2009 Nov 22. PMID:19935683[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Thienpont B, Zhang L, Postma AV, Breckpot J, Tranchevent LC, Van Loo P, Mollgard K, Tommerup N, Bache I, Tumer Z, van Engelen K, Menten B, Mortier G, Waggoner D, Gewillig M, Moreau Y, Devriendt K, Larsen LA. Haploinsufficiency of TAB2 causes congenital heart defects in humans. Am J Hum Genet. 2010 Jun 11;86(6):839-49. doi: 10.1016/j.ajhg.2010.04.011. Epub, 2010 May 20. PMID:20493459 doi:10.1016/j.ajhg.2010.04.011
  2. ↑ Takaesu G, Kishida S, Hiyama A, Yamaguchi K, Shibuya H, Irie K, Ninomiya-Tsuji J, Matsumoto K. TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway. Mol Cell. 2000 Apr;5(4):649-58. PMID:10882101
  3. ↑ Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature. 2001 Jul 19;412(6844):346-51. PMID:11460167 doi:10.1038/35085597
  4. ↑ Thienpont B, Zhang L, Postma AV, Breckpot J, Tranchevent LC, Van Loo P, Mollgard K, Tommerup N, Bache I, Tumer Z, van Engelen K, Menten B, Mortier G, Waggoner D, Gewillig M, Moreau Y, Devriendt K, Larsen LA. Haploinsufficiency of TAB2 causes congenital heart defects in humans. Am J Hum Genet. 2010 Jun 11;86(6):839-49. doi: 10.1016/j.ajhg.2010.04.011. Epub, 2010 May 20. PMID:20493459 doi:10.1016/j.ajhg.2010.04.011
  5. ↑ Kulathu Y, Akutsu M, Bremm A, Hofmann K, Komander D. Two-sided ubiquitin binding explains specificity of the TAB2 NZF domain. Nat Struct Mol Biol. 2009 Dec;16(12):1328-30. Epub 2009 Nov 22. PMID:19935683 doi:10.1038/nsmb.1731

Contents


PDB ID 2wx1

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OCA

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