PDBsum entry 1iyf

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protein links
Ligase PDB id
Protein chain
76 a.a. *
* Residue conservation analysis
PDB id:
Name: Ligase
Title: Solution structure of ubiquitin-like domain of human parkin
Structure: Parkin. Chain: a. Fragment: ubiquitin-like domain. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
NMR struc: 10 models
Authors: E.Sakata,Y.Yamaguchi,E.Kurimoto,J.Kikuchi,S.Yokoyama, H.Kawahara,H.Yokosawa,N.Hattori,Y.Mizuno,K.Tanaka,K.Kato, Riken Structural Genomics/proteomics Initiative (Rsgi)
Key ref:
E.Sakata et al. (2003). Parkin binds the Rpn10 subunit of 26S proteasomes through its ubiquitin-like domain. EMBO Rep, 4, 301-306. PubMed id: 12634850 DOI: 10.1038/sj.embor.embor764
13-Aug-02     Release date:   25-Mar-03    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
O60260  (PRKN2_HUMAN) -  E3 ubiquitin-protein ligase parkin
465 a.a.
76 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     mitochondrion   2 terms 
  Biochemical function     acid-amino acid ligase activity     2 terms  


DOI no: 10.1038/sj.embor.embor764 EMBO Rep 4:301-306 (2003)
PubMed id: 12634850  
Parkin binds the Rpn10 subunit of 26S proteasomes through its ubiquitin-like domain.
E.Sakata, Y.Yamaguchi, E.Kurimoto, J.Kikuchi, S.Yokoyama, S.Yamada, H.Kawahara, H.Yokosawa, N.Hattori, Y.Mizuno, K.Tanaka, K.Kato.
Parkin, a product of the causative gene of autosomal-recessive juvenile parkinsonism (AR-JP), is a RING-type E3 ubiquitin ligase and has an amino-terminal ubiquitin-like (Ubl) domain. Although a single mutation that causes an Arg to Pro substitution at position 42 of the Ubl domain (the Arg 42 mutation) has been identified in AR-JP patients, the function of this domain is not clear. In this study, we determined the three-dimensional structure of the Ubl domain of parkin by NMR, in particular by extensive use of backbone (15)N-(1)H residual dipolar-coupling data. Inspection of chemical-shift-perturbation data showed that the parkin Ubl domain binds the Rpn10 subunit of 26S proteasomes via the region of parkin that includes position 42. Our findings suggest that the Arg 42 mutation induces a conformational change in the Rpn10-binding site of Ubl, resulting in impaired proteasomal binding of parkin, which could be the cause of AR-JP.
  Selected figure(s)  
Figure 1.
Figure 1 The solution structure of the ubiquitin-like (Ubl) domain of parkin. (A) Stereo view of ten converged structures of the parkin Ubl domain. (B) Ribbon representation of the average structure. -strands and -helices are coloured yellow and pink, respectively, in (A) and (B). Numbers in (A) and (B) indicate amino-acid positions in the Ubl domain sequence. (C) Sequence alignment and secondary-structure elements of the parkin Ubl domain and ubiquitin.
Figure 2.
Figure 2 Identification of the binding site for Rpn10[196 -306] in the parkin ubiquitin-like (Ubl) domain. (A) 1H-15N heteronuclear single-quantum coherence (HSQC) spectrum of the parkin Ubl domain in the presence (red) and absence (black) of equimolar quantities of Rpn10[196 -306]. The peaks labelled with L-2, G-1 and S0 originate from the amino-terminal tag. (B) NMR chemical-shift-perturbation data for the parkin Ubl domain. The data are displayed for each residue according to the equation (0.2 [N]2 + [H]2)1/2, where [N] and [H] represent the change in nitrogen and proton chemical shifts on addition of Rpn10[196 -306]. Asterisks indicate residues the peaks of which became undetectable due to broadening. Secondary structure elements for the parkin Ubl are shown below the graph. (C) Mapping of the perturbed residues of the Ubl domains of parkin and PLIC2 (Walters et al., 2002) on binding to Rpn10. Residues showing a chemical-shift-perturbation are coloured in red, with the colour gradient indicating the strength of the perturbation. Residues the peaks of which became undetectable on binding to Rpn10 are shown in purple.
  The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO Rep (2003, 4, 301-306) copyright 2003.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21415856 M.P.Luna-Vargas, A.C.Faesen, W.J.van Dijk, M.Rape, A.Fish, and T.K.Sixma (2011).
Ubiquitin-specific protease 4 is inhibited by its ubiquitin-like domain.
  EMBO Rep, 12, 365-372.
PDB code: 2y6e
21348451 S.S.Safadi, K.R.Barber, and G.S.Shaw (2011).
Impact of autosomal recessive juvenile Parkinson's disease mutations on the structure and interactions of the parkin ubiquitin-like domain.
  Biochemistry, 50, 2603-2610.  
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.  
20696900 G.Poulogiannis, R.E.McIntyre, M.Dimitriadi, J.R.Apps, C.H.Wilson, K.Ichimura, F.Luo, L.C.Cantley, A.H.Wyllie, D.J.Adams, and M.J.Arends (2010).
PARK2 deletions occur frequently in sporadic colorectal cancer and accelerate adenoma development in Apc mutant mice.
  Proc Natl Acad Sci U S A, 107, 15145-15150.  
  20717473 H.C.Tai, H.Besche, A.L.Goldberg, and E.M.Schuman (2010).
Characterization of the Brain 26S Proteasome and its Interacting Proteins.
  Front Mol Neurosci, 3, 0.  
20541996 J.M.Winget, and T.Mayor (2010).
The diversity of ubiquitin recognition: hot spots and varied specificity.
  Mol Cell, 38, 627-635.  
20131003 Q.Huang, and M.E.Figueiredo-Pereira (2010).
Ubiquitin/proteasome pathway impairment in neurodegeneration: therapeutic implications.
  Apoptosis, 15, 1292-1311.  
19875440 S.S.Safadi, and G.S.Shaw (2010).
Differential interaction of the E3 ligase parkin with the proteasomal subunit S5a and the endocytic protein Eps15.
  J Biol Chem, 285, 1424-1434.  
19946270 S.Veeriah, B.S.Taylor, S.Meng, F.Fang, E.Yilmaz, I.Vivanco, M.Janakiraman, N.Schultz, A.J.Hanrahan, W.Pao, M.Ladanyi, C.Sander, A.Heguy, E.C.Holland, P.B.Paty, P.S.Mischel, L.Liau, T.F.Cloughesy, I.K.Mellinghoff, D.B.Solit, and T.A.Chan (2010).
Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies.
  Nat Genet, 42, 77-82.  
18834306 A.L.Schwartz, and A.Ciechanover (2009).
Targeting proteins for destruction by the ubiquitin system: implications for human pathobiology.
  Annu Rev Pharmacol Toxicol, 49, 73-96.  
19489727 D.Finley (2009).
Recognition and processing of ubiquitin-protein conjugates by the proteasome.
  Annu Rev Biochem, 78, 477-513.  
20064467 D.Zhang, T.Chen, I.Ziv, R.Rosenzweig, Y.Matiuhin, V.Bronner, M.H.Glickman, and D.Fushman (2009).
Together, Rpn10 and Dsk2 can serve as a polyubiquitin chain-length sensor.
  Mol Cell, 36, 1018-1033.  
19841631 E.K.Schrader, K.G.Harstad, and A.Matouschek (2009).
Targeting proteins for degradation.
  Nat Chem Biol, 5, 815-822.  
20064468 J.F.Trempe, C.X.Chen, K.Grenier, E.M.Camacho, G.Kozlov, P.S.McPherson, K.Gehring, and E.A.Fon (2009).
SH3 domains from a subset of BAR proteins define a Ubl-binding domain and implicate parkin in synaptic ubiquitination.
  Mol Cell, 36, 1034-1047.
PDB codes: 2knb 3iql
18671761 N.Dehvari, A.Sandebring, A.Flores-Morales, L.Mateos, Y.C.Chuan, M.S.Goldberg, M.R.Cookson, R.F.Cowburn, and A.Cedazo-Mínguez (2009).
Parkin-mediated ubiquitination regulates phospholipase C-gamma1.
  J Cell Mol Med, 13, 3061-3068.  
19796170 N.Yoshimoto, K.Tatematsu, T.Okajima, K.Tanizawa, and S.Kuroda (2009).
Accumulation of polyubiquitinated proteins by overexpression of RBCC protein interacting with protein kinase C2, a splice variant of ubiquitin ligase RBCC protein interacting with protein kinase C1.
  FEBS J, 276, 6375-6385.  
19339245 V.A.Hristova, S.A.Beasley, R.J.Rylett, and G.S.Shaw (2009).
Identification of a Novel Zn2+-binding Domain in the Autosomal Recessive Juvenile Parkinson-related E3 Ligase Parkin.
  J Biol Chem, 284, 14978-14986.  
19422283 Z.Yao, and N.W.Wood (2009).
Cell death pathways in Parkinson's disease: role of mitochondria.
  Antioxid Redox Signal, 11, 2135-2149.  
18248624 D.J.Moore, A.B.West, D.A.Dikeman, V.L.Dawson, and T.M.Dawson (2008).
Parkin mediates the degradation-independent ubiquitination of Hsp70.
  J Neurochem, 105, 1806-1819.  
18313759 F.J.Lee, and F.Liu (2008).
Genetic factors involved in the pathogenesis of Parkinson's disease.
  Brain Res Rev, 58, 354-364.  
18303026 K.Tatematsu, N.Yoshimoto, T.Okajima, K.Tanizawa, and S.Kuroda (2008).
Identification of ubiquitin ligase activity of RBCK1 and its inhibition by splice variant RBCK2 and protein kinase Cbeta.
  J Biol Chem, 283, 11575-11585.  
18283660 M.Zouambia, D.F.Fischer, B.Hobo, R.A.De Vos, E.M.Hol, I.M.Varndell, P.W.Sheppard, and F.W.Van Leeuwen (2008).
Proteasome subunit proteins and neuropathology in tauopathies and synucleinopathies: Consequences for proteomic analyses.
  Proteomics, 8, 1221-1236.  
19033459 T.D.Helton, T.Otsuka, M.C.Lee, Y.Mu, and M.D.Ehlers (2008).
Pruning and loss of excitatory synapses by the parkin ubiquitin ligase.
  Proc Natl Acad Sci U S A, 105, 19492-19497.  
18995839 Y.Matiuhin, D.S.Kirkpatrick, I.Ziv, W.Kim, A.Dakshinamurthy, O.Kleifeld, S.P.Gygi, N.Reis, and M.H.Glickman (2008).
Extraproteasomal Rpn10 restricts access of the polyubiquitin-binding protein Dsk2 to proteasome.
  Mol Cell, 32, 415-425.  
18426756 Y.Mizuno, N.Hattori, S.Kubo, S.Sato, K.Nishioka, T.Hatano, H.Tomiyama, M.Funayama, Y.Machida, and H.Mochizuki (2008).
Progress in the pathogenesis and genetics of Parkinson's disease.
  Philos Trans R Soc Lond B Biol Sci, 363, 2215-2227.  
17472700 E.Kyratzi, M.Pavlaki, D.Kontostavlaki, H.J.Rideout, and L.Stefanis (2007).
Differential effects of Parkin and its mutants on protein aggregation, the ubiquitin-proteasome system, and neuronal cell death in human neuroblastoma cells.
  J Neurochem, 102, 1292-1303.  
17329252 E.S.Wong, J.M.Tan, C.Wang, Z.Zhang, S.P.Tay, N.Zaiden, H.S.Ko, V.L.Dawson, T.M.Dawson, and K.L.Lim (2007).
Relative sensitivity of parkin and other cysteine-containing enzymes to stress-induced solubility alterations.
  J Biol Chem, 282, 12310-12318.  
17911097 H.Yi, J.L.Friedman, and P.A.Ferreira (2007).
The cyclophilin-like domain of Ran-binding protein-2 modulates selectively the activity of the ubiquitin-proteasome system and protein biogenesis.
  J Biol Chem, 282, 34770-34778.  
18047733 L.Madsen, A.Schulze, M.Seeger, and R.Hartmann-Petersen (2007).
Ubiquitin domain proteins in disease.
  BMC Biochem, 8, S1.  
18052765 M.Di Napoli, I.M.Shah, and D.A.Stewart (2007).
Molecular pathways and genetic aspects of Parkinson's disease: from bench to bedside.
  Expert Rev Neurother, 7, 1693-1729.  
17668154 Y.Tayama, H.Kawahara, R.Minami, M.Shimada, and H.Yokosawa (2007).
Association of Rpn10 with high molecular weight complex is enhanced during retinoic acid-induced differentiation of neuroblastoma cells.
  Mol Cell Biochem, 306, 53-57.  
16972273 C.W.Olanow, and K.S.McNaught (2006).
Ubiquitin-proteasome system and Parkinson's disease.
  Mov Disord, 21, 1806-1823.  
16973374 E.Schurr, A.Alcaïs, Léséleuc, and L.Abel (2006).
Genetic predisposition to leprosy: A major gene reveals novel pathways of immunity to Mycobacterium leprae.
  Semin Immunol, 18, 404-410.  
16328510 H.F.Chien, C.F.Rohé, M.D.Costa, G.J.Breedveld, B.A.Oostra, E.R.Barbosa, and V.Bonifati (2006).
Early-onset Parkinson's disease caused by a novel parkin mutation in a genetic isolate from north-eastern Brazil.
  Neurogenetics, 7, 13-19.  
16455660 H.Jiang, Q.Jiang, W.Liu, and J.Feng (2006).
Parkin suppresses the expression of monoamine oxidases.
  J Biol Chem, 281, 8591-8599.  
16837855 L.D.Jensen, T.Vinther-Jensen, S.Kahns, S.Sundbye, and P.H.Jensen (2006).
Cellular parkin mutants are soluble under non-stress conditions.
  Neuroreport, 17, 1205-1208.  
16501224 M.C.Tettamanzi, C.Yu, J.S.Bogan, and M.E.Hodsdon (2006).
Solution structure and backbone dynamics of an N-terminal ubiquitin-like domain in the GLUT4-regulating protein, TUG.
  Protein Sci, 15, 498-508.
PDB code: 2al3
17047309 M.W.Wooten, X.Hu, J.R.Babu, M.L.Seibenhener, T.Geetha, M.G.Paine, and M.C.Wooten (2006).
Signaling, Polyubiquitination, Trafficking, and Inclusions: Sequestosome 1/p62's Role in Neurodegenerative Disease.
  J Biomed Biotechnol, 2006, 62079.  
16978147 O.A.Buneeva, and A.E.Medvedev (2006).
Ubiquitin-protein ligase parkin and its role in the development of Parkinson's disease.
  Biochemistry (Mosc), 71, 851-860.  
16495942 P.M.Abou-Sleiman, M.M.Muqit, and N.W.Wood (2006).
Expanding insights of mitochondrial dysfunction in Parkinson's disease.
  Nat Rev Neurosci, 7, 207-219.  
16615060 S.Kubo, N.Hattori, and Y.Mizuno (2006).
Recessive Parkinson's disease.
  Mov Disord, 21, 885-893.  
16987221 Y.X.Yang, M.M.Muqit, and D.S.Latchman (2006).
Induction of parkin expression in the presence of oxidative stress.
  Eur J Neurosci, 24, 1366-1372.  
15557340 A.Yamamoto, A.Friedlein, Y.Imai, R.Takahashi, P.J.Kahle, and C.Haass (2005).
Parkin phosphorylation and modulation of its E3 ubiquitin ligase activity.
  J Biol Chem, 280, 3390-3399.  
16022590 D.J.Moore, A.B.West, V.L.Dawson, and T.M.Dawson (2005).
Molecular pathophysiology of Parkinson's disease.
  Annu Rev Neurosci, 28, 57-87.  
15684050 F.A.Perez, and R.D.Palmiter (2005).
Parkin-deficient mice are not a robust model of parkinsonism.
  Proc Natl Acad Sci U S A, 102, 2174-2179.  
16375772 F.A.Perez, W.R.Curtis, and R.D.Palmiter (2005).
Parkin-deficient mice are not more sensitive to 6-hydroxydopamine or methamphetamine neurotoxicity.
  BMC Neurosci, 6, 71.  
15606901 I.H.Henn, J.M.Gostner, P.Lackner, J.Tatzelt, and K.F.Winklhofer (2005).
Pathogenic mutations inactivate parkin by distinct mechanisms.
  J Neurochem, 92, 114-122.  
15952880 M.R.Cookson (2005).
The biochemistry of Parkinson's disease.
  Annu Rev Biochem, 74, 29-52.  
16201867 M.Schmidt, J.Hanna, S.Elsasser, and D.Finley (2005).
Proteasome-associated proteins: regulation of a proteolytic machine.
  Biol Chem, 386, 725-737.  
15780906 R.Farràs, G.Bossis, E.Andermarcher, I.Jariel-Encontre, and M.Piechaczyk (2005).
Mechanisms of delivery of ubiquitylated proteins to the proteasome: new target for anti-cancer therapy?
  Crit Rev Oncol Hematol, 54, 31-51.  
16064136 R.L.Welchman, C.Gordon, and R.J.Mayer (2005).
Ubiquitin and ubiquitin-like proteins as multifunctional signals.
  Nat Rev Mol Cell Biol, 6, 599-609.  
16056265 S.Elsasser, and D.Finley (2005).
Delivery of ubiquitinated substrates to protein-unfolding machines.
  Nat Cell Biol, 7, 742-749.  
15987890 Y.G.Gao, A.X.Song, Y.H.Shi, Y.G.Chang, S.X.Liu, Y.Z.Yu, X.T.Cao, D.H.Lin, and H.Y.Hu (2005).
Solution structure of the ubiquitin-like domain of human DC-UbP from dendritic cells.
  Protein Sci, 14, 2044-2050.
PDB code: 1ttn
16336274 Y.Kikukawa, R.Minami, M.Shimada, M.Kobayashi, K.Tanaka, H.Yokosawa, and H.Kawahara (2005).
Unique proteasome subunit Xrpn10c is a specific receptor for the antiapoptotic ubiquitin-like protein Scythe.
  FEBS J, 272, 6373-6386.  
15090075 A.F.Haywood, and B.E.Staveley (2004).
Parkin counteracts symptoms in a Drosophila model of Parkinson's disease.
  BMC Neurosci, 5, 14.  
15312912 A.N.Hegde (2004).
Ubiquitin-proteasome-mediated local protein degradation and synaptic plasticity.
  Prog Neurobiol, 73, 311-357.  
15280365 B.E.Riley, Y.Xu, H.Y.Zoghbi, and H.T.Orr (2004).
The effects of the polyglutamine repeat protein ataxin-1 on the UbL-UBA protein A1Up.
  J Biol Chem, 279, 42290-42301.  
15496406 C.Gorbea, G.M.Goellner, K.Teter, R.K.Holmes, and M.Rechsteiner (2004).
Characterization of mammalian Ecm29, a 26 S proteasome-associated protein that localizes to the nucleus and membrane vesicles.
  J Biol Chem, 279, 54849-54861.  
15272266 E.Bossy-Wetzel, R.Schwarzenbacher, and S.A.Lipton (2004).
Molecular pathways to neurodegeneration.
  Nat Med, 10, S2-S9.  
15294138 J.Shen, and M.R.Cookson (2004).
Mitochondria and dopamine: new insights into recessive parkinsonism.
  Neuron, 43, 301-304.  
14585839 K.Fujiwara, T.Tenno, K.Sugasawa, J.G.Jee, I.Ohki, C.Kojima, H.Tochio, H.Hiroaki, F.Hanaoka, and M.Shirakawa (2004).
Structure of the ubiquitin-interacting motif of S5a bound to the ubiquitin-like domain of HR23B.
  J Biol Chem, 279, 4760-4767.
PDB code: 1uel
15319427 M.J.May, S.E.Larsen, J.H.Shim, L.A.Madge, and S.Ghosh (2004).
A novel ubiquitin-like domain in IkappaB kinase beta is required for functional activity of the kinase.
  J Biol Chem, 279, 45528-45539.  
15325839 N.Hattori, and Y.Mizuno (2004).
Pathogenetic mechanisms of parkin in Parkinson's disease.
  Lancet, 364, 722-724.  
15229644 P.J.Kahle, and C.Haass (2004).
How does parkin ligate ubiquitin to Parkinson's disease?
  EMBO Rep, 5, 681-685.  
15209385 R.Hartmann-Petersen, and C.Gordon (2004).
Integral UBL domain proteins: a family of proteasome interacting proteins.
  Semin Cell Dev Biol, 15, 247-259.  
15572841 R.Takahashi (2004).
[Neurodegeneration caused by ER stress?--the pathogenetic mechanisms underlying AR-JP]
  Nippon Yakurigaku Zasshi, 124, 375-382.  
15242647 R.Verma, R.Oania, J.Graumann, and R.J.Deshaies (2004).
Multiubiquitin chain receptors define a layer of substrate selectivity in the ubiquitin-proteasome system.
  Cell, 118, 99.  
15102845 S.L.Chan, W.Fu, P.Zhang, A.Cheng, J.Lee, K.Kokame, and M.P.Mattson (2004).
Herp stabilizes neuronal Ca2+ homeostasis and mitochondrial function during endoplasmic reticulum stress.
  J Biol Chem, 279, 28733-28743.  
15194120 Y.Imai, and R.Takahashi (2004).
How do Parkin mutations result in neurodegeneration?
  Curr Opin Neurobiol, 14, 384-389.  
12937272 H.C.Ardley, G.B.Scott, S.A.Rose, N.G.Tan, A.F.Markham, and P.A.Robinson (2003).
Inhibition of proteasomal activity causes inclusion formation in neuronal and non-neuronal cells overexpressing Parkin.
  Mol Biol Cell, 14, 4541-4556.  
12970172 K.A.Swanson, R.S.Kang, S.D.Stamenova, L.Hicke, and I.Radhakrishnan (2003).
Solution structure of Vps27 UIM-ubiquitin complex important for endosomal sorting and receptor downregulation.
  EMBO J, 22, 4597-4606.
PDB codes: 1q0v 1q0w
12886009 M.R.Cookson (2003).
Crystallizing ideas about Parkinson's disease.
  Proc Natl Acad Sci U S A, 100, 9111-9113.  
12842030 M.R.Cookson (2003).
Neurodegeneration: how does parkin prevent Parkinson's disease?
  Curr Biol, 13, R522-R524.  
14581452 P.S.Bilodeau, S.C.Winistorfer, W.R.Kearney, A.D.Robertson, and R.C.Piper (2003).
Vps27-Hse1 and ESCRT-I complexes cooperate to increase efficiency of sorting ubiquitinated proteins at the endosome.
  J Cell Biol, 163, 237-243.  
12970176 T.D.Mueller, and J.Feigon (2003).
Structural determinants for the binding of ubiquitin-like domains to the proteasome.
  EMBO J, 22, 4634-4645.
PDB codes: 1p98 1p9c 1p9d
12676955 Y.C.Tsai, P.S.Fishman, N.V.Thakor, and G.A.Oyler (2003).
Parkin facilitates the elimination of expanded polyglutamine proteins and leads to preservation of proteasome function.
  J Biol Chem, 278, 22044-22055.  
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.