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PDBsum entry 2vhf

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protein metals Protein-protein interface(s) links
Hydrolase PDB id
2vhf
Jmol
Contents
Protein chains
341 a.a. *
334 a.a. *
Metals
_ZN ×4
Waters ×14
* Residue conservation analysis
PDB id:
2vhf
Name: Hydrolase
Title: Structure of the cyld usp domain
Structure: Ubiquitin carboxyl-terminal hydrolase cyld. Chain: a, b. Fragment: usp deubiquitinase domain, residues 583-956. Synonym: ubiquitin thioesterase cyld, ubiquitin-specific -processing protease cyld, deubiquitinating enzyme cyld, cyld. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
Resolution:
2.80Å     R-factor:   0.235     R-free:   0.281
Authors: D.Komander,C.J.Lord,H.Scheel,S.Swift,K.Hofmann,A.Ashworth, D.Barford
Key ref:
D.Komander et al. (2008). The structure of the CYLD USP domain explains its specificity for Lys63-linked polyubiquitin and reveals a B box module. Mol Cell, 29, 451-464. PubMed id: 18313383 DOI: 10.1016/j.molcel.2007.12.018
Date:
21-Nov-07     Release date:   11-Mar-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
No UniProt id for this chain
Struc: 341 a.a.
Protein chain
Pfam   ArchSchema ?
Q9NQC7  (CYLD_HUMAN) -  Ubiquitin carboxyl-terminal hydrolase CYLD
Seq:
Struc:
 
Seq:
Struc:
956 a.a.
334 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chain B: E.C.3.4.19.12  - 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!
  Biological process     ubiquitin-dependent protein catabolic process   1 term 
  Biochemical function     ?     1 term  

 

 
DOI no: 10.1016/j.molcel.2007.12.018 Mol Cell 29:451-464 (2008)
PubMed id: 18313383  
 
 
The structure of the CYLD USP domain explains its specificity for Lys63-linked polyubiquitin and reveals a B box module.
D.Komander, C.J.Lord, H.Scheel, S.Swift, K.Hofmann, A.Ashworth, D.Barford.
 
  ABSTRACT  
 
The tumor suppressor CYLD antagonizes NF-kappaB and JNK signaling by disassembly of Lys63-linked ubiquitin chains synthesized in response to cytokine stimulation. Here we describe the crystal structure of the CYLD USP domain, revealing a distinctive architecture that provides molecular insights into its specificity toward Lys63-linked polyubiquitin. We identify regions of the USP domain responsible for this specificity and demonstrate endodeubiquitinase activity toward such chains. Pathogenic truncations of the CYLD C terminus, associated with the hypertrophic skin tumor cylindromatosis, disrupt the USP domain, accounting for loss of CYLD catalytic activity. A small zinc-binding B box domain, similar in structure to other crossbrace Zn-binding folds--including the RING domain found in E3 ubiquitin ligases--is inserted within the globular core of the USP domain. Biochemical and functional characterization of the B box suggests a role as a protein-interaction module that contributes to determining the subcellular localization of CYLD.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Structure of the CYLD USP Domain
(A) The CYLD USP domain is shown in cartoon representation, and subdomains are indicated in blue (Thumb), green (truncated Fingers), cyan (Palm), and red (B box). The C-terminal 20 amino acids, truncated in some cylindromatosis patients, are colored orange. Gray dotted lines indicate disordered loops. The two Zn atoms are shown as yellow spheres, and the Cys-His-Asp catalytic triad residues are shown.
(B) Structure of HAUSP using the same color scheme. Secondary structure elements in the Fingers domain that are not present in CYLD are labeled.
(C) Superposition of CYLD as in (A), with a yellow semitransparent model of active HAUSP. The molecules were superposed in coot (RMSD of 2.7 Å over 223 residues).
Figure 2.
Figure 2. Analysis of Structural Conservation between the CYLD and HAUSP USP Domains
(A) Structure-based sequence alignment highlighting conserved residues. Secondary structure elements are colored according to Figure 1A and labeled according to HAUSP. Gray elements correspond to the Fingers domain in HAUSP, and the B box insertion (residues 786–853) in CYLD including the eight Zn coordinating residues is shown in red. Disordered regions in molecule A are indicated by dotted lines. Residues of the catalytic triad and oxyanion hole are indicated with red and blue arrows, respectively, whereas conserved residues that contact ubiquitin are indicated with an orange arrow. Sequence alignment figures were prepared with Alscript (Barton, 1993).
(B) Conservation between CYLD, HAUSP, USP14, USP2, and Ubp6 is mapped onto the HAUSP surface with color ramp from white (nonconserved) to blue (conserved), and the ubiquitin molecule (from HAUSP) is shown in yellow. On the ubiquitin molecule, Lys63 and Lys48 are shown. The most conserved region comprises the channel that binds the C terminus of the distal ubiquitin. For a full alignment, refer to Figure S1.
(C) The conservation as in (B) is mapped onto the CYLD surface. The ubiquitin molecule from HAUSP is depicted; superposition of HAUSP (1nbf) and CYLD was performed in COOT.
 
  The above figures are reprinted by permission from Cell Press: Mol Cell (2008, 29, 451-464) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20972631 A.M.van den Ouweland, P.Elfferich, R.Lamping, R.van de Graaf, M.M.van Veghel-Plandsoen, S.M.Franken, and A.C.Houweling (2011).
Identification of a large rearrangement in CYLD as a cause of familial cylindromatosis.
  Fam Cancer, 10, 127-132.  
21135870 C.Zheng, Q.Yin, and H.Wu (2011).
Structural studies of NF-κB signaling.
  Cell Res, 21, 183-195.  
21119682 E.W.Harhaj, and V.M.Dixit (2011).
Deubiquitinases in the regulation of NF-κB signaling.
  Cell Res, 21, 22-39.  
21151032 L.Bedford, J.Lowe, L.R.Dick, R.J.Mayer, and J.E.Brownell (2011).
Ubiquitin-like protein conjugation and the ubiquitin-proteasome system as drug targets.
  Nat Rev Drug Discov, 10, 29-46.  
21411309 L.Frappier, and C.P.Verrijzer (2011).
Gene expression control by protein deubiquitinases.
  Curr Opin Genet Dev, 21, 207-213.  
21345146 R.Massoumi (2011).
CYLD: a deubiquitination enzyme with multiple roles in cancer.
  Future Oncol, 7, 285-297.  
20622874 A.Bremm, S.M.Freund, and D.Komander (2010).
Lys11-linked ubiquitin chains adopt compact conformations and are preferentially hydrolyzed by the deubiquitinase Cezanne.
  Nat Struct Mol Biol, 17, 939-947.
PDB code: 2xew
20434206 A.Köhler, E.Zimmerman, M.Schneider, E.Hurt, and N.Zheng (2010).
Structural basis for assembly and activation of the heterotetrameric SAGA histone H2B deubiquitinase module.
  Cell, 141, 606-617.
PDB code: 3m99
20739285 C.Riedinger, J.Boehringer, J.F.Trempe, E.D.Lowe, N.R.Brown, K.Gehring, M.E.Noble, C.Gordon, and J.A.Endicott (2010).
Structure of Rpn10 and its interactions with polyubiquitin chains and the proteasome subunit Rpn12.
  J Biol Chem, 285, 33992-34003.
PDB code: 2x5n
20227366 D.V.Tauriello, A.Haegebarth, I.Kuper, M.J.Edelmann, M.Henraat, M.R.Canninga-van Dijk, B.M.Kessler, H.Clevers, and M.M.Maurice (2010).
Loss of the tumor suppressor CYLD enhances Wnt/beta-catenin signaling through K63-linked ubiquitination of Dvl.
  Mol Cell, 37, 607-619.  
20595234 E.J.Song, S.L.Werner, J.Neubauer, F.Stegmeier, J.Aspden, D.Rio, J.W.Harper, S.J.Elledge, M.W.Kirschner, and M.Rape (2010).
The Prp19 complex and the Usp4Sart3 deubiquitinating enzyme control reversible ubiquitination at the spliceosome.
  Genes Dev, 24, 1434-1447.  
  20838651 I.Kouranti, J.R.McLean, A.Feoktistova, P.Liang, A.E.Johnson, R.H.Roberts-Galbraith, and K.L.Gould (2010).
A global census of fission yeast deubiquitinating enzyme localization and interaction networks reveals distinct compartmentalization profiles and overlapping functions in endocytosis and polarity.
  PLoS Biol, 8, 0.  
20502939 J.Gautheron, and G.Courtois (2010).
"Without Ub I am nothing": NEMO as a multifunctional player in ubiquitin-mediated control of NF-kappaB activation.
  Cell Mol Life Sci, 67, 3101-3113.  
19373246 S.C.Sun (2010).
CYLD: a tumor suppressor deubiquitinase regulating NF-kappaB activation and diverse biological processes.
  Cell Death Differ, 17, 25-34.  
20802491 S.Virdee, Y.Ye, D.P.Nguyen, D.Komander, and J.W.Chin (2010).
Engineered diubiquitin synthesis reveals Lys29-isopeptide specificity of an OTU deubiquitinase.
  Nat Chem Biol, 6, 750-757.
PDB code: 2xk5
19373254 D.Komander, F.Reyes-Turcu, J.D.Licchesi, P.Odenwaelder, K.D.Wilkinson, and D.Barford (2009).
Molecular discrimination of structurally equivalent Lys 63-linked and linear polyubiquitin chains.
  EMBO Rep, 10, 466-473.
PDB codes: 2jf5 2w9n
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.  
19214193 E.M.Cooper, C.Cutcliffe, T.Z.Kristiansen, A.Pandey, C.M.Pickart, and R.E.Cohen (2009).
K63-specific deubiquitination by two JAMM/MPN+ complexes: BRISC-associated Brcc36 and proteasomal Poh1.
  EMBO J, 28, 621-631.  
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.  
19773779 I.Dikic, S.Wakatsuki, and K.J.Walters (2009).
Ubiquitin-binding domains - from structures to functions.
  Nat Rev Mol Cell Biol, 10, 659-671.  
19462465 P.W.Blake, and J.R.Toro (2009).
Update of cylindromatosis gene (CYLD) mutations in Brooke-Spiegler syndrome: novel insights into the role of deubiquitination in cell signaling.
  Hum Mutat, 30, 1025-1036.  
19303852 S.Rahighi, F.Ikeda, M.Kawasaki, M.Akutsu, N.Suzuki, R.Kato, T.Kensche, T.Uejima, S.Bloor, D.Komander, F.Randow, S.Wakatsuki, and I.Dikic (2009).
Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation.
  Cell, 136, 1098-1109.
PDB codes: 2zvn 2zvo 3f89
19281271 Y.H.Chiu, M.Zhao, and Z.J.Chen (2009).
Ubiquitin in NF-kappaB signaling.
  Chem Rev, 109, 1549-1560.  
19536136 Y.Sato, A.Yoshikawa, H.Mimura, M.Yamashita, A.Yamagata, and S.Fukai (2009).
Structural basis for specific recognition of Lys 63-linked polyubiquitin chains by tandem UIMs of RAP80.
  EMBO J, 28, 2461-2468.
PDB code: 3a1q
19927120 Y.Sato, A.Yoshikawa, M.Yamashita, A.Yamagata, and S.Fukai (2009).
Structural basis for specific recognition of Lys 63-linked polyubiquitin chains by NZF domains of TAB2 and TAB3.
  EMBO J, 28, 3903-3909.
PDB codes: 3a9j 3a9k
19675569 Z.P.Xia, L.Sun, X.Chen, G.Pineda, X.Jiang, A.Adhikari, W.Zeng, and Z.J.Chen (2009).
Direct activation of protein kinases by unanchored polyubiquitin chains.
  Nature, 461, 114-119.  
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.  
18482987 F.E.Reyes-Turcu, J.R.Shanks, D.Komander, and K.D.Wilkinson (2008).
Recognition of polyubiquitin isoforms by the multiple ubiquitin binding modules of isopeptidase T.
  J Biol Chem, 283, 19581-19592.  
19091944 H.Wang, A.Matsuzawa, S.A.Brown, J.Zhou, C.S.Guy, P.H.Tseng, K.Forbes, T.P.Nicholson, P.W.Sheppard, H.Häcker, M.Karin, and D.A.Vignali (2008).
Analysis of nondegradative protein ubiquitylation with a monoclonal antibody specific for lysine-63-linked polyubiquitin.
  Proc Natl Acad Sci U S A, 105, 20197-20202.  
18535581 S.C.Sun (2008).
Deubiquitylation and regulation of the immune response.
  Nat Rev Immunol, 8, 501-511.  
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.