2ffw

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Solution structure of the RBCC/TRIM B-box1 domain of human MID1: B-box with a RING

Structural highlights

2ffw is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Solution NMR
Ligands:ZN
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TRI18_HUMAN Defects in MID1 are the cause of Opitz GBBB syndrome 1 (OGS1) [MIM:300000. A congenital midline malformation syndrome characterized by hypertelorism, genital-urinary defects such as hypospadias in males and splayed labia in females, lip-palate-laryngotracheal clefts, imperforate anus, developmental delay and congenital heart defects. Note=MID1 mutations produce proteins with a decreased affinity for microtubules.[1] [2] [3] [4]

Function

TRI18_HUMAN Has E3 ubiquitin ligase activity towards IGBP1, promoting its monoubiquitination, which results in deprotection of the catalytic subunit of protein phosphatase PP2A, and its subsequent degradation by polyubiquitination.[5] [6] [7]

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

B-box domains are a defining feature of the tripartite RBCC (RING, B-box, coiled-coil) or TRIM proteins, many of which are E3 ubiquitin ligases. However, little is known about the biological function of B-boxes. In some RBCC/TRIM proteins there is only a single B-box (type 2) domain, while others have both type 1 and type 2 B-box domains in tandem adjacent to their RING domain. These two types of B-boxes share little sequence similarity, except the presence of cysteine and histidine residues: eight in most B-box1 domains and seven in B-box2 domains. We report here the high-resolution solution structure of the first B-box1 domain (from the human RBCC protein, MID1) based on 670 nuclear Overhauser effect (NOE)-derived distance restraints, 12 hydrogen bonds, and 44 dihedral angles. The domain consists of a three-turn alpha-helix, two short beta-strands, and three beta-turns, encompassing Val117 to Pro164, which binds two zinc atoms. One zinc atom is coordinated by cysteine residues 119, 122, 142, 145, while cysteine 134, 137 and histidine 150, 159 coordinate the other. This topology is markedly different from the only other B-box structure reported; that of a type 2 B-box from Xenopus XNF7, which binds a single zinc atom. Of note, the B-box1 structure closely resembles the folds of the RING, ZZ and U-box domains of E3 and E4 ubiquitin enzymes, raising the possibility that the B-box1 domain either has E3 activity itself or enhances the activity of RING type E3 ligases (i.e. confers E4 enzyme activity). The structure of the MID1 B-box1 also reveals two potential protein interaction surfaces. One of these is likely to provide the binding interface for Alpha 4 that is required for the localized turnover of the catalytic subunit of PP2A, the major Ser/Thr phosphatase.

Solution structure of the RBCC/TRIM B-box1 domain of human MID1: B-box with a RING.,Massiah MA, Simmons BN, Short KM, Cox TC J Mol Biol. 2006 Apr 28;358(2):532-45. Epub 2006 Feb 20. PMID:16529770[8]

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

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References

  1. ↑ Quaderi NA, Schweiger S, Gaudenz K, Franco B, Rugarli EI, Berger W, Feldman GJ, Volta M, Andolfi G, Gilgenkrantz S, Marion RW, Hennekam RC, Opitz JM, Muenke M, Ropers HH, Ballabio A. Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22. Nat Genet. 1997 Nov;17(3):285-91. PMID:9354791 doi:10.1038/ng1197-285
  2. ↑ Cox TC, Allen LR, Cox LL, Hopwood B, Goodwin B, Haan E, Suthers GK. New mutations in MID1 provide support for loss of function as the cause of X-linked Opitz syndrome. Hum Mol Genet. 2000 Oct 12;9(17):2553-62. PMID:11030761
  3. ↑ Gaudenz K, Roessler E, Quaderi N, Franco B, Feldman G, Gasser DL, Wittwer B, Horst J, Montini E, Opitz JM, Ballabio A, Muenke M. Opitz G/BBB syndrome in Xp22: mutations in the MID1 gene cluster in the carboxy-terminal domain. Am J Hum Genet. 1998 Sep;63(3):703-10. PMID:9718340
  4. ↑ So J, Suckow V, Kijas Z, Kalscheuer V, Moser B, Winter J, Baars M, Firth H, Lunt P, Hamel B, Meinecke P, Moraine C, Odent S, Schinzel A, van der Smagt JJ, Devriendt K, Albrecht B, Gillessen-Kaesbach G, van der Burgt I, Petrij F, Faivre L, McGaughran J, McKenzie F, Opitz JM, Cox T, Schweiger S. Mild phenotypes in a series of patients with Opitz GBBB syndrome with MID1 mutations. Am J Med Genet A. 2005 Jan 1;132A(1):1-7. PMID:15558842 doi:10.1002/ajmg.a.30407
  5. ↑ Cainarca S, Messali S, Ballabio A, Meroni G. Functional characterization of the Opitz syndrome gene product (midin): evidence for homodimerization and association with microtubules throughout the cell cycle. Hum Mol Genet. 1999 Aug;8(8):1387-96. PMID:10400985
  6. ↑ Trockenbacher A, Suckow V, Foerster J, Winter J, Krauss S, Ropers HH, Schneider R, Schweiger S. MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation. Nat Genet. 2001 Nov;29(3):287-94. PMID:11685209 doi:10.1038/ng762
  7. ↑ Watkins GR, Wang N, Mazalouskas MD, Gomez RJ, Guthrie CR, Kraemer BC, Schweiger S, Spiller BW, Wadzinski BE. Monoubiquitination promotes calpain cleavage of the protein phosphatase 2A (PP2A) regulatory subunit alpha4, altering PP2A stability and microtubule-associated protein phosphorylation. J Biol Chem. 2012 Jul 13;287(29):24207-15. doi: 10.1074/jbc.M112.368613. Epub, 2012 May 21. PMID:22613722 doi:10.1074/jbc.M112.368613
  8. ↑ Massiah MA, Simmons BN, Short KM, Cox TC. Solution structure of the RBCC/TRIM B-box1 domain of human MID1: B-box with a RING. J Mol Biol. 2006 Apr 28;358(2):532-45. Epub 2006 Feb 20. PMID:16529770 doi:10.1016/j.jmb.2006.02.009

Contents


PDB ID 2ffw

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