PDBsum entry 1yzb

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protein links
Transcription PDB id
Protein chain
182 a.a. *
* Residue conservation analysis
PDB id:
Name: Transcription
Title: Solution structure of the josephin domain of ataxin-3
Structure: Machado-joseph disease protein 1. Chain: a. Fragment: n-terminal domain of ataxin-3. Synonym: ataxin-3, spinocerebellar ataxia type 3 protein. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
NMR struc: 10 models
Authors: G.Nicastro,L.Masino,R.P.Menon,P.P.Knowles,N.Q.Mcdonald, A.Pastore
Key ref:
G.Nicastro et al. (2005). The solution structure of the Josephin domain of ataxin-3: structural determinants for molecular recognition. Proc Natl Acad Sci U S A, 102, 10493-10498. PubMed id: 16020535 DOI: 10.1073/pnas.0501732102
28-Feb-05     Release date:   05-Jul-05    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P54252  (ATX3_HUMAN) -  Ataxin-3
364 a.a.
182 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Ubiquitinyl hydrolase 1.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Thiol-dependent hydrolysis of ester, thiolester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biochemical function     omega peptidase activity     1 term  


DOI no: 10.1073/pnas.0501732102 Proc Natl Acad Sci U S A 102:10493-10498 (2005)
PubMed id: 16020535  
The solution structure of the Josephin domain of ataxin-3: structural determinants for molecular recognition.
G.Nicastro, R.P.Menon, L.Masino, P.P.Knowles, N.Q.McDonald, A.Pastore.
The Josephin domain plays an important role in the cellular functions of ataxin-3, the protein responsible for the neurodegenerative Machado-Joseph disease. We have determined the solution structure of Josephin and shown that it belongs to the family of papain-like cysteine proteases, sharing the highest degree of structural similarity with bacterial staphopain. A currently unique structural feature of Josephin is a flexible helical hairpin formed by a 32-residue insertion, which could determine substrate specificity. By using the Josephin structure and the availability of NMR chemical shift assignments, we have mapped the enzyme active site by using the typical cysteine protease inhibitors, transepoxysuccinyl-L-eucylamido-4-guanidino-butane (E-64) and [L-3-trans-(propylcarbamyl)oxirane-2-carbonyl]-L-isoleucyl-L-proline (CA-074). We also demonstrate that the specific interaction of Josephin with the ubiquitin-like domain of the ubiquitin- and proteasome-binding factor HHR23B involves complementary exposed hydrophobic surfaces. The structural similarity with other deubiquitinating enzymes suggests a model for the proteolytic enzymatic activity of ataxin-3.
  Selected figure(s)  
Figure 2.
Fig. 2. Comparison between the Josephin structure with those of the Cys proteases staphopain (PDB ID code 1cv8 [PDB] ), avirulence protein (PDB ID code 1ukf [PDB] ), papain (PDB ID code 1pe6 [PDB] ), YUH1 (PDB ID code 1cmx [PDB] ), and UCH-L3 (PDB ID code 1uch [PDB] ). The side chains of the catalytic triad are shown on each structure.
Figure 4.
Fig. 4. Modeling of the interaction surfaces of Josephin with some of its molecular partners. (A) Model of the Josephin/HHR23B complex as built by HADDOCK. Josephin is shown in blue and magenta, and HHR23B Ubl domain is shown in gold and pale green (PDB ID code 1p1a [PDB] ). The side chains of the residues involved in the interaction are displayed. (B) Model of YUH1 (Left, PDB ID code 1cmx [PDB] ) and Josephin (Right) complexes with Ub-aldehyde. The YUH1 coordinates were used as a template to model the Josephin complex by fitting the coordinates of the two proteases according to the DALI superposition.
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21504740 L.Masino, G.Nicastro, A.De Simone, L.Calder, J.Molloy, and A.Pastore (2011).
The Josephin domain determines the morphological and mechanical properties of ataxin-3 fibrils.
  Biophys J, 100, 2033-2042.  
20810784 M.Laura, N.Giuseppe, C.Lesley, V.Michele, and P.Annalisa (2011).
Functional interactions as a survival strategy against abnormal aggregation.
  FASEB J, 25, 45-54.  
20940148 T.M.Durcan, M.Kontogiannea, T.Thorarinsdottir, L.Fallon, A.J.Williams, A.Djarmati, T.Fantaneanu, H.L.Paulson, and E.A.Fon (2011).
The Machado-Joseph disease-associated mutant form of ataxin-3 regulates parkin ubiquitination and stability.
  Hum Mol Genet, 20, 141-154.  
21047872 Y.W.Chen, T.Tajima, and S.Agrawal (2011).
The crystal structure of the ubiquitin-like (UbL) domain of human homologue A of Rad23 (hHR23A) protein.
  Protein Eng Des Sel, 24, 131-138.
PDB code: 2wyq
20484674 A.L.Robertson, S.J.Headey, H.M.Saunders, H.Ecroyd, M.J.Scanlon, J.A.Carver, and S.P.Bottomley (2010).
Small heat-shock proteins interact with a flanking domain to suppress polyglutamine aggregation.
  Proc Natl Acad Sci U S A, 107, 10424-10429.  
19843543 C.P.Reina, X.Zhong, and R.N.Pittman (2010).
Proteotoxic stress increases nuclear localization of ataxin-3.
  Hum Mol Genet, 19, 235-249.  
20865150 G.Nicastro, S.V.Todi, E.Karaca, A.M.Bonvin, H.L.Paulson, and A.Pastore (2010).
Understanding the role of the Josephin domain in the PolyUb binding and cleavage properties of ataxin-3.
  PLoS One, 5, e12430.  
20308049 S.Alves, I.Nascimento-Ferreira, N.Dufour, R.Hassig, G.Auregan, C.Nóbrega, E.Brouillet, P.Hantraye, M.C.Pedroso de Lima, N.Déglon, and Almeida (2010).
Silencing ataxin-3 mitigates degeneration in a rat model of Machado-Joseph disease: no role for wild-type ataxin-3?
  Hum Mol Genet, 19, 2380-2394.  
20100826 S.Ishii, T.Yano, A.Ebihara, A.Okamoto, M.Manzoku, and H.Hayashi (2010).
Crystal structure of the peptidase domain of Streptococcus ComA, a bifunctional ATP-binding cassette transporter involved in the quorum-sensing pathway.
  J Biol Chem, 285, 10777-10785.
PDB code: 3k8u
19626045 D.Komander, M.J.Clague, and S.Urbé (2009).
Breaking the chains: structure and function of the deubiquitinases.
  Nat Rev Mol Cell Biol, 10, 550-563.  
19243136 F.E.Reyes-Turcu, and K.D.Wilkinson (2009).
Polyubiquitin binding and disassembly by deubiquitinating enzymes.
  Chem Rev, 109, 1495-1508.  
19489724 F.E.Reyes-Turcu, K.H.Ventii, and K.D.Wilkinson (2009).
Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes.
  Annu Rev Biochem, 78, 363-397.  
19382171 G.Nicastro, L.Masino, V.Esposito, R.P.Menon, A.De Simone, F.Fraternali, and A.Pastore (2009).
Josephin domain of ataxin-3 contains two distinct ubiquitin-binding sites.
  Biopolymers, 91, 1203-1214.  
19666135 S.Mazzucchelli, A.De Palma, M.Riva, A.D'Urzo, C.Pozzi, V.Pastori, F.Comelli, P.Fusi, M.Vanoni, P.Tortora, P.Mauri, and M.E.Regonesi (2009).
Proteomic and biochemical analyses unveil tight interaction of ataxin-3 with tubulin.
  Int J Biochem Cell Biol, 41, 2485-2492.  
19153604 S.V.Todi, B.J.Winborn, K.M.Scaglione, J.R.Blount, S.M.Travis, and H.L.Paulson (2009).
Ubiquitination directly enhances activity of the deubiquitinating enzyme ataxin-3.
  EMBO J, 28, 372-382.  
18599482 B.J.Winborn, S.M.Travis, S.V.Todi, K.M.Scaglione, P.Xu, A.J.Williams, R.E.Cohen, J.Peng, and H.L.Paulson (2008).
The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits Lys63 linkages in mixed linkage ubiquitin chains.
  J Biol Chem, 283, 26436-26443.  
18250627 K.U.Wendt, M.S.Weiss, P.Cramer, and D.W.Heinz (2008).
Structures and diseases.
  Nat Struct Mol Biol, 15, 117-120.  
18418689 O.Riess, U.Rüb, A.Pastore, P.Bauer, and L.Schöls (2008).
SCA3: Neurological features, pathogenesis and animal models.
  Cerebellum, 7, 125-137.  
19036964 X.Chen, T.S.Tang, H.Tu, O.Nelson, M.Pook, R.Hammer, N.Nukina, and I.Bezprozvanny (2008).
Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 3.
  J Neurosci, 28, 12713-12724.  
17300980 F.Ricchelli, P.Fusi, P.Tortora, M.Valtorta, M.Riva, G.Tognon, K.Chieregato, S.Bolognin, and P.Zatta (2007).
Destabilization of non-pathological variants of ataxin-3 by metal ions results in aggregation/fibrillogenesis.
  Int J Biochem Cell Biol, 39, 966-977.  
17417937 H.T.Orr, and H.Y.Zoghbi (2007).
Trinucleotide repeat disorders.
  Annu Rev Neurosci, 30, 575-621.  
18047739 J.E.Davies, S.Sarkar, and D.C.Rubinsztein (2007).
The ubiquitin proteasome system in Huntington's disease and the spinocerebellar ataxias.
  BMC Biochem, 8, S2.  
18047733 L.Madsen, A.Schulze, M.Seeger, and R.Hartmann-Petersen (2007).
Ubiquitin domain proteins in disease.
  BMC Biochem, 8, S1.  
17696782 N.Tzvetkov, and P.Breuer (2007).
Josephin domain-containing proteins from a variety of species are active de-ubiquitination enzymes.
  Biol Chem, 388, 973-978.  
17899394 S.W.Ginzinger, F.Gerick, M.Coles, and V.Heun (2007).
CheckShift: automatic correction of inconsistent chemical shift referencing.
  J Biomol NMR, 39, 223-227.  
17632007 V.F.Colomer Gould, D.Goti, D.Pearce, G.A.Gonzalez, H.Gao, M.Bermudez de Leon, N.A.Jenkins, N.G.Copeland, C.A.Ross, and D.R.Brown (2007).
A mutant ataxin-3 fragment results from processing at a site N-terminal to amino acid 190 in brain of Machado-Joseph disease-like transgenic mice.
  Neurobiol Dis, 27, 362-369.  
17096206 G.Nicastro, M.Habeck, L.Masino, D.I.Svergun, and A.Pastore (2006).
Structure validation of the Josephin domain of ataxin-3: conclusive evidence for an open conformation.
  J Biomol NMR, 36, 267-277.  
16939621 P.L.Mauri, M.Riva, D.Ambu, A.De Palma, F.Secundo, L.Benazzi, M.Valtorta, P.Tortora, and P.Fusi (2006).
Ataxin-3 is subject to autolytic cleavage.
  FEBS J, 273, 4277-4286.  
16913834 T.Sulea, H.A.Lindner, and R.Ménard (2006).
Structural aspects of recently discovered viral deubiquitinating activities.
  Biol Chem, 387, 853-862.  
16325574 S.M.Nijman, M.P.Luna-Vargas, A.Velds, T.R.Brummelkamp, A.M.Dirac, T.K.Sixma, and R.Bernards (2005).
A genomic and functional inventory of deubiquitinating enzymes.
  Cell, 123, 773-786.  
16118278 Y.Mao, F.Senic-Matuglia, P.P.Di Fiore, S.Polo, M.E.Hodsdon, and P.De Camilli (2005).
Deubiquitinating function of ataxin-3: insights from the solution structure of the Josephin domain.
  Proc Natl Acad Sci U S A, 102, 12700-12705.
PDB code: 2aga
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 code is shown on the right.