PDBsum entry 1k2f

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protein ligands metals Protein-protein interface(s) links
Ligase, protein binding PDB id
Protein chains
190 a.a. *
BME ×4
_ZN ×6
Waters ×65
* Residue conservation analysis
PDB id:
Name: Ligase, protein binding
Title: Siah, seven in absentia homolog
Structure: Siah-1a protein. Chain: a, b. Fragment: c-terminal domain (residues 93-282). Synonym: seven in absentia 1a. Engineered: yes
Source: Mus musculus. House mouse. Organism_taxid: 10090. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Dimer (from PQS)
2.60Å     R-factor:   0.220     R-free:   0.277
Authors: G.Polekhina,C.M.House,N.Traficante,J.P.Mackay,F.Relaix, D.A.Sassoon,M.W.Parker,D.D.L.Bowtell
Key ref:
G.Polekhina et al. (2002). Siah ubiquitin ligase is structurally related to TRAF and modulates TNF-alpha signaling. Nat Struct Biol, 9, 68-75. PubMed id: 11742346 DOI: 10.1038/nsb743
26-Sep-01     Release date:   28-Dec-01    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P61092  (SIA1A_MOUSE) -  E3 ubiquitin-protein ligase SIAH1A
282 a.a.
190 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     multicellular organismal development   3 terms 
  Biochemical function     ubiquitin-protein ligase activity     2 terms  


DOI no: 10.1038/nsb743 Nat Struct Biol 9:68-75 (2002)
PubMed id: 11742346  
Siah ubiquitin ligase is structurally related to TRAF and modulates TNF-alpha signaling.
G.Polekhina, C.M.House, N.Traficante, J.P.Mackay, F.Relaix, D.A.Sassoon, M.W.Parker, D.D.Bowtell.
Members of the Siah (seven in absentia homolog) family of RING domain proteins are components of E3 ubiquitin ligase complexes that catalyze ubiquitination of proteins. We have determined the crystal structure of the substrate-binding domain (SBD) of murine Siah1a to 2.6 A resolution. The structure reveals that Siah is a dimeric protein and that the SBD adopts an eight-stranded beta-sandwich fold that is highly similar to the TRAF-C region of TRAF (TNF-receptor associated factor) proteins. The TRAF-C region interacts with TNF-alpha receptors and TNF-receptor associated death-domain (TRADD) proteins; however, our findings indicate that these interactions are unlikely to be mimicked by Siah. The Siah structure also reveals two novel zinc fingers in a region with sequence similarity to TRAF. We find that the Siah1a SBD potentiates TNF-alpha-mediated NF-kappa B activation. Therefore, Siah proteins share important similarities with the TRAF family of proteins, including their overall domain architecture, three-dimensional structure and functional activity.
  Selected figure(s)  
Figure 4.
Figure 4. Similarities between Siah and TRAF. a, Comparison of the domain architecture of Siah and TRAF2 proteins. Pink circle represents the RING domain; blue bar, zinc finger; red rod, coiled-coil; and green rod, TRAF-C domain. b, Siah1a SBD stimulation of an NF- B reporter assay in 293 cells. Cells were transfected with Siah1a, Siah1a SBD, TRAF2 or TNF- and combinations of TNF- -Siah1a and TNF- -Siah1a SBD. Cotransfection of the I B super repressor was able to reduce NF- B activation to background levels for all points measured (data not shown).
Figure 5.
Figure 5. Surface features of Siah SBD. a, Surface of Siah1a SBD dimer with the zinc fingers shown in blue and the C-terminal domains in green. Areas of strictly conserved residues are shown in red. b,c, Views of SBD after successive 90 rotations along the long axis of the molecule. A putative RING interacting region (see text) is indicated by the arrows in (a,c). A star in (b) highlights a potential binding partner/substrate site (see text). Images were generated by GRASP60.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2002, 9, 68-75) copyright 2002.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19940145 E.C.Yego, and S.Mohr (2010).
siah-1 Protein is necessary for high glucose-induced glyceraldehyde-3-phosphate dehydrogenase nuclear accumulation and cell death in Muller cells.
  J Biol Chem, 285, 3181-3190.  
  20144232 H.Bruzzoni-Giovanelli, P.Fernandez, L.Veiga, M.P.Podgorniak, D.J.Powell, M.M.Candeias, S.Mourah, F.Calvo, and M.Marín (2010).
Distinct expression patterns of the E3 ligase SIAH-1 and its partner Kid/KIF22 in normal tissues and in the breast tumoral processes.
  J Exp Clin Cancer Res, 29, 10.  
  21037926 J.Qi, and Z.A.Ronai (2010).
The Siah2-HIF-FoxA2 axis in prostate cancer - new markers and therapeutic opportunities.
  Oncotarget, 1, 379-385.  
20634198 S.Zucchelli, M.Codrich, F.Marcuzzi, M.Pinto, S.Vilotti, M.Biagioli, I.Ferrer, and S.Gustincich (2010).
TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson's disease brains.
  Hum Mol Genet, 19, 3759-3770.  
18850011 A.Möller, C.M.House, C.S.Wong, D.B.Scanlon, M.C.Liu, Z.Ronai, and D.D.Bowtell (2009).
Inhibition of Siah ubiquitin ligase function.
  Oncogene, 28, 289-296.  
19818708 M.Zhuang, M.F.Calabrese, J.Liu, M.B.Waddell, A.Nourse, M.Hammel, D.J.Miller, H.Walden, D.M.Duda, S.N.Seyedin, T.Hoggard, J.W.Harper, K.P.White, and B.A.Schulman (2009).
Structures of SPOP-substrate complexes: insights into molecular architectures of BTB-Cul3 ubiquitin ligases.
  Mol Cell, 36, 39-50.
PDB codes: 3hqh 3hqi 3hql 3hqm 3hsv 3htm 3hu6 3hve 3ivq 3ivv
19489725 R.J.Deshaies, and C.A.Joazeiro (2009).
RING domain E3 ubiquitin ligases.
  Annu Rev Biochem, 78, 399-434.  
19224863 R.Szargel, R.Rott, A.Eyal, J.Haskin, V.Shani, L.Balan, H.Wolosker, and S.Engelender (2009).
Synphilin-1A Inhibits Seven in Absentia Homolog (SIAH) and Modulates {alpha}-Synuclein Monoubiquitylation and Inclusion Formation.
  J Biol Chem, 284, 11706-11716.  
19440308 V.Moresi, G.Garcia-Alvarez, A.Pristerà, E.Rizzuto, M.C.Albertini, M.Rocchi, G.Marazzi, D.Sassoon, S.Adamo, and D.Coletti (2009).
Modulation of caspase activity regulates skeletal muscle regeneration and function in response to vasopressin and tumor necrosis factor.
  PLoS ONE, 4, e5570.  
19001609 A.U.Ahmed, R.L.Schmidt, C.H.Park, N.R.Reed, S.E.Hesse, C.F.Thomas, J.R.Molina, C.Deschamps, P.Yang, M.C.Aubry, and A.H.Tang (2008).
Effect of disrupting seven-in-absentia homolog 2 function on lung cancer cell growth.
  J Natl Cancer Inst, 100, 1606-1629.  
19033658 F.Sheikh, A.Raskin, P.H.Chu, S.Lange, A.A.Domenighetti, M.Zheng, X.Liang, T.Zhang, T.Yajima, Y.Gu, N.D.Dalton, S.K.Mahata, G.W.Dorn, J.Heller-Brown, K.L.Peterson, J.H.Omens, A.D.McCulloch, and J.Chen (2008).
An FHL1-containing complex within the cardiomyocyte sarcomere mediates hypertrophic biomechanical stress responses in mice.
  J Clin Invest, 118, 3870-3880.  
18515172 I.E.Wertz, and V.M.Dixit (2008).
Ubiquitin-mediated regulation of TNFR1 signaling.
  Cytokine Growth Factor Rev, 19, 313-324.  
18536714 M.Winter, D.Sombroek, I.Dauth, J.Moehlenbrink, K.Scheuermann, J.Crone, and T.G.Hofmann (2008).
Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR.
  Nat Cell Biol, 10, 812-824.  
18463287 S.Alper, R.Laws, B.Lackford, W.A.Boyd, P.Dunlap, J.H.Freedman, and D.A.Schwartz (2008).
Identification of innate immunity genes and pathways using a comparative genomics approach.
  Proc Natl Acad Sci U S A, 105, 7016-7021.  
17533377 A.Depaux, F.Regnier-Ricard, A.Germani, and N.Varin-Blank (2007).
A crosstalk between hSiah2 and Pias E3-ligases modulates Pias-dependent activation.
  Oncogene, 26, 6665-6676.  
17983264 C.H.Yeang, and D.Haussler (2007).
Detecting coevolution in and among protein domains.
  PLoS Comput Biol, 3, e211.  
17420721 Y.Mei, C.Xie, W.Xie, Z.Wu, and M.Wu (2007).
Siah-1S, a novel splice variant of Siah-1 (seven in absentia homolog), counteracts Siah-1-mediated downregulation of beta-catenin.
  Oncogene, 26, 6319-6331.  
16964245 G.J.Gutierrez, A.Vögtlin, A.Castro, I.Ferby, G.Salvagiotto, Z.Ronai, T.Lorca, and A.R.Nebreda (2006).
Meiotic regulation of the CDK activator RINGO/Speedy by ubiquitin-proteasome-mediated processing and degradation.
  Nat Cell Biol, 8, 1084-1094.  
16510976 J.L.Jenkins, and J.J.Tanner (2006).
High-resolution structure of human D-glyceraldehyde-3-phosphate dehydrogenase.
  Acta Crystallogr D Biol Crystallogr, 62, 290-301.
PDB codes: 1u8f 2feh
16230351 Z.Xu, A.Sproul, W.Wang, N.Kukekov, and L.A.Greene (2006).
Siah1 interacts with the scaffold protein POSH to promote JNK activation and apoptosis.
  J Biol Chem, 281, 303-312.  
16085652 E.Santelli, M.Leone, C.Li, T.Fukushima, N.E.Preece, A.J.Olson, K.R.Ely, J.C.Reed, M.Pellecchia, R.C.Liddington, and S.Matsuzawa (2005).
Structural analysis of Siah1-Siah-interacting protein interactions and insights into the assembly of an E3 ligase multiprotein complex.
  J Biol Chem, 280, 34278-34287.
PDB codes: 2a25 2a26
15937930 K.L.Kenyon, D.J.Li, C.Clouser, S.Tran, and F.Pignoni (2005).
Fly SIX-type homeodomain proteins Sine oculis and Optix partner with different cofactors during eye development.
  Dev Dyn, 234, 497-504.  
15808506 V.Saridakis, Y.Sheng, F.Sarkari, M.N.Holowaty, K.Shire, T.Nguyen, R.G.Zhang, J.Liao, W.Lee, A.M.Edwards, C.H.Arrowsmith, and L.Frappier (2005).
Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediated immortalization.
  Mol Cell, 18, 25-36.
PDB codes: 1yy6 1yze
15466852 H.Habelhah, A.Laine, H.Erdjument-Bromage, P.Tempst, M.E.Gershwin, D.D.Bowtell, and Z.Ronai (2004).
Regulation of 2-oxoglutarate (alpha-ketoglutarate) dehydrogenase stability by the RING finger ubiquitin ligase Siah.
  J Biol Chem, 279, 53782-53788.  
15123657 I.J.Frew, N.A.Sims, J.M.Quinn, C.R.Walkley, L.E.Purton, D.D.Bowtell, and M.T.Gillespie (2004).
Osteopenia in Siah1a mutant mice.
  J Biol Chem, 279, 29583-29588.  
14645235 M.Fanelli, A.Fantozzi, P.De Luca, S.Caprodossi, S.Matsuzawa, M.A.Lazar, P.G.Pelicci, and S.Minucci (2004).
The coiled-coil domain is the structural determinant for mammalian homologues of Drosophila Sina-mediated degradation of promyelocytic leukemia protein and other tripartite motif proteins by the proteasome.
  J Biol Chem, 279, 5374-5379.  
15459319 P.L.Oliver, E.Bitoun, J.Clark, E.L.Jones, and K.E.Davies (2004).
Mediation of Af4 protein function in the cerebellum by Siah proteins.
  Proc Natl Acad Sci U S A, 101, 14901-14906.  
12626763 C.M.House, I.J.Frew, H.L.Huang, G.Wiche, N.Traficante, E.Nice, B.Catimel, and D.D.Bowtell (2003).
A binding motif for Siah ubiquitin ligase.
  Proc Natl Acad Sci U S A, 100, 3101-3106.  
14645526 I.J.Frew, V.E.Hammond, R.A.Dickins, J.M.Quinn, C.R.Walkley, N.A.Sims, R.Schnall, N.G.Della, A.J.Holloway, M.R.Digby, P.W.Janes, D.M.Tarlinton, L.E.Purton, M.T.Gillespie, and D.D.Bowtell (2003).
Generation and analysis of Siah2 mutant mice.
  Mol Cell Biol, 23, 9150-9161.  
12819136 J.C.Reed, K.Doctor, A.Rojas, J.M.Zapata, C.Stehlik, L.Fiorentino, J.Damiano, W.Roth, S.Matsuzawa, R.Newman, S.Takayama, H.Marusawa, F.Xu, G.Salvesen, and A.Godzik (2003).
Comparative analysis of apoptosis and inflammation genes of mice and humans.
  Genome Res, 13, 1376-1388.  
12421809 S.Matsuzawa, C.Li, C.Z.Ni, S.Takayama, J.C.Reed, and K.R.Ely (2003).
Structural analysis of Siah1 and its interactions with Siah-interacting protein (SIP).
  J Biol Chem, 278, 1837-1840.  
12527760 S.S.Krishna, I.Majumdar, and N.V.Grishin (2003).
Structural classification of zinc fingers: survey and summary.
  Nucleic Acids Res, 31, 532-550.  
11847111 D.Coletti, E.Yang, G.Marazzi, and D.Sassoon (2002).
TNFalpha inhibits skeletal myogenesis through a PW1-dependent pathway by recruitment of caspase pathways.
  EMBO J, 21, 631-642.  
12411493 H.Habelhah, I.J.Frew, A.Laine, P.W.Janes, F.Relaix, D.Sassoon, D.D.Bowtell, and Z.Ronai (2002).
Stress-induced decrease in TRAF2 stability is mediated by Siah2.
  EMBO J, 21, 5756-5765.  
11753426 J.C.Reed, and K.R.Ely (2002).
Degrading liaisons: Siah structure revealed.
  Nat Struct Biol, 9, 8.  
11943780 M.D.Johnson, X.Wu, N.Aithmitti, and R.S.Morrison (2002).
Peg3/Pw1 is a mediator between p53 and Bax in DNA damage-induced neuronal death.
  J Biol Chem, 277, 23000-23007.  
12097341 O.Lespinet, Y.I.Wolf, E.V.Koonin, and L.Aravind (2002).
The role of lineage-specific gene family expansion in the evolution of eukaryotes.
  Genome Res, 12, 1048-1059.  
12226665 Q.Xie, H.S.Guo, G.Dallman, S.Fang, A.M.Weissman, and N.H.Chua (2002).
SINAT5 promotes ubiquitin-related degradation of NAC1 to attenuate auxin signals.
  Nature, 419, 167-170.  
12215542 S.Li, C.Xu, and R.W.Carthew (2002).
Phyllopod acts as an adaptor protein to link the sina ubiquitin ligase to the substrate protein tramtrack.
  Mol Cell Biol, 22, 6854-6865.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.