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PDBsum entry 2zej

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protein ligands metals Protein-protein interface(s) links
Transferase PDB id
2zej
Jmol PyMol
Contents
Protein chain
157 a.a. *
Ligands
GDP ×2
Metals
_MG ×2
Waters ×113
* Residue conservation analysis
PDB id:
2zej
Name: Transferase
Title: Structure of the roc domain from the parkinson's disease-ass leucine-rich repeat kinase 2 reveals a dimeric gtpase
Structure: Leucine-rich repeat kinase 2. Chain: a, b. Fragment: roc-gtpase domain, unp residues 1333-1516. Synonym: dardarin. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: lrrk2. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.00Å     R-factor:   0.202     R-free:   0.253
Authors: J.Deng
Key ref:
J.Deng et al. (2008). Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase. Proc Natl Acad Sci U S A, 105, 1499-1504. PubMed id: 18230735 DOI: 10.1073/pnas.0709098105
Date:
13-Dec-07     Release date:   22-Jan-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q5S007  (LRRK2_HUMAN) -  Leucine-rich repeat serine/threonine-protein kinase 2
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
2527 a.a.
157 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.7.11.1  - Non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
=
ADP
Bound ligand (Het Group name = GDP)
matches with 96.43% similarity
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     small GTPase mediated signal transduction   1 term 
  Biochemical function     GTP binding     1 term  

 

 
    reference    
 
 
DOI no: 10.1073/pnas.0709098105 Proc Natl Acad Sci U S A 105:1499-1504 (2008)
PubMed id: 18230735  
 
 
Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase.
J.Deng, P.A.Lewis, E.Greggio, E.Sluch, A.Beilina, M.R.Cookson.
 
  ABSTRACT  
 
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of Parkinson's disease (PD). LRRK2 contains a Ras of complex proteins (ROC) domain that may act as a GTPase to regulate its protein kinase activity. The structure of ROC and the mechanism(s) by which it regulates kinase activity are not known. Here, we report the crystal structure of the LRRK2 ROC domain in complex with GDP-Mg(2+) at 2.0-A resolution. The structure displays a dimeric fold generated by extensive domain-swapping, resulting in a pair of active sites constructed with essential functional groups contributed from both monomers. Two PD-associated pathogenic residues, R1441 and I1371, are located at the interface of two monomers and provide exquisite interactions to stabilize the ROC dimer. The structure demonstrates that loss of stabilizing forces in the ROC dimer is likely related to decreased GTPase activity resulting from mutations at these sites. Our data suggest that the ROC domain may regulate LRRK2 kinase activity as a dimer, possibly via the C-terminal of ROC (COR) domain as a molecular hinge. The structure of the LRRK2 ROC domain also represents a signature from a previously undescribed class of GTPases from complex proteins and results may provide a unique molecular target for therapeutics in PD.
 
  Selected figure(s)  
 
Figure 1.
The unique dimeric ROC GTPase. (A) Stereoview of the domain-swapped dimer. The two individual monomers are shown in yellow and green. The GDP-Mg^2+ ligands are shown in ball-and-stick format. (B) Ribbon representation of a single monomer. The three head, neck, and body subdomains are indicated, along with the labeled secondary structures. The P-loop, G3/Switch II, and G4 and G5 loops are indicated in orange, pink, red, and cyan, respectively. The disordered G2 loop is shown as a black dotted curve. (C) Surface representation highlighting the GDP-Mg^2+ binding pocket on the surface of the dimer that is contributed from both monomers. The pair of functional units are shown as ROCs1 and ROCs2, respectively.
Figure 2.
Structural basis of PD-associated mutations in ROC. (A) R1441 and W1434 from one monomer together with F1401 and P1406 from the other stack on each other alternately, forming a hydrophobic zipper at the dimer interface. The guanidinium group of R1441 also is hydrogen-bonded with the backbone carbonyl oxygen of F1401 and the hydroxyl group of T1404 on helix α2 from the other peptide chain. 2mF [o] − DF [c] electron density map is shown in blue. (B) I1371 is inserted in a hydrophobic cavity, which is constructed by residues from both monomers at the dimer interface. I1371 is shown in stick format and colored in orange. The surrounding residues are shown in stick format within the semitransparent surface representation. The color scheme is the same as that in Fig. 1. Note the side-chain methyl group of T1404 is pointing directly to the tip of I1371, forming a favorable van der Waals' interaction. (C) R1441C (lane 3), as a prototypical mutation at the dimer interface, decreases interaction with the full-length wild-type LRRK2 protein compared with wild-type GST fusions (lane 2); no interaction was seen with GST alone (lane 1). (D) Pull-down assays were quantified and corrected for the amount of LRRK2 protein in the inputs (middle blots). *, P < 0.0001; **, P < 0.01 compared with GST alone (one-way ANOVA with Student–Newman–Kuell's post hoc test; n = 3).
 
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22728659 Y.H.Huang, X.Y.Liu, X.X.Du, Z.F.Jiang, and X.D.Su (2012).
The structural basis for the sensing and binding of cyclic di-GMP by STING.
  Nat Struct Mol Biol, 19, 728-730.
PDB codes: 4f5d 4f5e
  21199179 E.K.Tan, and A.H.Schapira (2011).
LRRK2 as a therapeutic target in Parkinson's disease.
  Eur J Neurol, 18, 545-546.  
21439347 H.M.Gao, and J.S.Hong (2011).
Gene-environment interactions: Key to unraveling the mystery of Parkinson's disease.
  Prog Neurobiol, 94, 1.  
21073465 V.Daniëls, R.Vancraenenbroeck, B.M.Law, E.Greggio, E.Lobbestael, F.Gao, M.De Maeyer, M.R.Cookson, K.Harvey, V.Baekelandt, and J.M.Taymans (2011).
Insight into the mode of action of the LRRK2 Y1699C pathogenic mutant.
  J Neurochem, 116, 304-315.  
21390248 X.Li, Q.J.Wang, N.Pan, S.Lee, Y.Zhao, B.T.Chait, and Z.Yue (2011).
Phosphorylation-dependent 14-3-3 binding to LRRK2 is impaired by common mutations of familial Parkinson's disease.
  PLoS One, 6, e17153.  
20443975 C.B.Abdalla-Carvalho, C.B.Santos-Rebouças, B.C.Guimarães, M.Campos, J.S.Pereira, A.L.de Rosso, D.H.Nicaretta, M.Marinho e Silva, M.J.dos Santos, and M.M.Pimentel (2010).
Genetic analysis of LRRK2 functional domains in Brazilian patients with Parkinson's disease.
  Eur J Neurol, 17, 1479-1481.  
20173330 C.H.Hsu, D.Chan, and B.Wolozin (2010).
LRRK2 and the stress response: interaction with MKKs and JNK-interacting proteins.
  Neurodegener Dis, 7, 68-75.  
20576132 D.Kerk, and G.B.Moorhead (2010).
A phylogenetic survey of myotubularin genes of eukaryotes: distribution, protein structure, evolution, and gene expression.
  BMC Evol Biol, 10, 196.  
20127702 J.M.Taymans, and M.R.Cookson (2010).
Mechanisms in dominant parkinsonism: The toxic triangle of LRRK2, alpha-synuclein, and tau.
  Bioessays, 32, 227-235.  
20669305 J.O.Aasly, C.Vilariño-Güell, J.C.Dachsel, P.J.Webber, A.B.West, K.Haugarvoll, K.K.Johansen, M.Toft, J.G.Nutt, H.Payami, J.M.Kachergus, S.J.Lincoln, A.Felic, C.Wider, A.I.Soto-Ortolaza, S.A.Cobb, L.R.White, O.A.Ross, and M.J.Farrer (2010).
Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease.
  Mov Disord, 25, 2156-2163.  
20653510 P.A.Robinson (2010).
Understanding the molecular basis of Parkinson's disease, identification of biomarkers and routes to therapy.
  Expert Rev Proteomics, 7, 565-578.  
21060682 P.P.Pungaliya, Y.Bai, K.Lipinski, V.S.Anand, S.Sen, E.L.Brown, B.Bates, P.H.Reinhart, A.B.West, W.D.Hirst, and S.P.Braithwaite (2010).
Identification and characterization of a leucine-rich repeat kinase 2 (LRRK2) consensus phosphorylation motif.
  PLoS One, 5, e13672.  
20187256 W.Dauer, and C.C.Ho (2010).
The biology and pathology of the familial Parkinson's disease protein LRRK2.
  Mov Disord, 25, S40-S43.  
20457918 Y.Tong, H.Yamaguchi, E.Giaime, S.Boyle, R.Kopan, R.J.Kelleher, and J.Shen (2010).
Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of alpha-synuclein, and apoptotic cell death in aged mice.
  Proc Natl Acad Sci U S A, 107, 9879-9884.  
20386743 Y.Xiong, C.E.Coombes, A.Kilaru, X.Li, A.D.Gitler, W.J.Bowers, V.L.Dawson, T.M.Dawson, and D.J.Moore (2010).
GTPase activity plays a key role in the pathobiology of LRRK2.
  PLoS Genet, 6, e1000902.  
19756366 A.Thaler, E.Ash, Z.Gan-Or, A.Orr-Urtreger, and N.Giladi (2009).
The LRRK2 G2019S mutation as the cause of Parkinson's disease in Ashkenazi Jews.
  J Neural Transm, 116, 1473-1482.  
19302196 C.J.Gloeckner, A.Schumacher, K.Boldt, and M.Ueffing (2009).
The Parkinson disease-associated protein kinase LRRK2 exhibits MAPKKK activity and phosphorylates MKK3/6 and MKK4/7, in vitro.
  J Neurochem, 109, 959-968.  
19712061 C.L.Klein, G.Rovelli, W.Springer, C.Schall, T.Gasser, and P.J.Kahle (2009).
Homo- and heterodimerization of ROCO kinases: LRRK2 kinase inhibition by the LRRK2 ROCO fragment.
  J Neurochem, 111, 703-715.  
19472409 C.Paisán-Ruiz (2009).
LRRK2 gene variation and its contribution to Parkinson disease.
  Hum Mutat, 30, 1153-1160.  
19733152 E.Greggio, J.M.Taymans, E.Y.Zhen, J.Ryder, R.Vancraenenbroeck, A.Beilina, P.Sun, J.Deng, H.Jaffe, V.Baekelandt, K.Merchant, and M.R.Cookson (2009).
The Parkinson's disease kinase LRRK2 autophosphorylates its GTPase domain at multiple sites.
  Biochem Biophys Res Commun, 389, 449-454.  
  19570025 E.Greggio, and M.R.Cookson (2009).
Leucine-rich repeat kinase 2 mutations and Parkinson's disease: three questions.
  ASN Neuro, 1, 0.  
19142648 G.Santpere, and I.Ferrer (2009).
LRRK2 and neurodegeneration.
  Acta Neuropathol, 117, 227-246.  
19640926 J.Alegre-Abarrategui, H.Christian, M.M.Lufino, R.Mutihac, L.L.Venda, O.Ansorge, and R.Wade-Martins (2009).
LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model.
  Hum Mol Genet, 18, 4022-4034.  
19721815 J.L.George, S.Mok, D.Moses, S.Wilkins, A.I.Bush, R.A.Cherny, and D.I.Finkelstein (2009).
Targeting the progression of Parkinson's disease.
  Curr Neuropharmacol, 7, 9.  
20041156 N.D.Jorgensen, Y.Peng, C.C.Ho, H.J.Rideout, D.Petrey, P.Liu, and W.T.Dauer (2009).
The WD40 domain is required for LRRK2 neurotoxicity.
  PLoS One, 4, e8463.  
19025767 P.N.Gandhi, S.G.Chen, and A.L.Wilson-Delfosse (2009).
Leucine-rich repeat kinase 2 (LRRK2): a key player in the pathogenesis of Parkinson's disease.
  J Neurosci Res, 87, 1283-1295.  
19424291 R.Gasper, S.Meyer, K.Gotthardt, M.Sirajuddin, and A.Wittinghofer (2009).
It takes two to tango: regulation of G proteins by dimerization.
  Nat Rev Mol Cell Biol, 10, 423-429.  
18973807 S.Biskup, and A.B.West (2009).
Zeroing in on LRRK2-linked pathogenic mechanisms in Parkinson's disease.
  Biochim Biophys Acta, 1792, 625-633.  
19826009 S.Sen, P.J.Webber, and A.B.West (2009).
Dependence of leucine-rich repeat kinase 2 (LRRK2) kinase activity on dimerization.
  J Biol Chem, 284, 36346-36356.  
19536328 X.Ding, and M.S.Goldberg (2009).
Regulation of LRRK2 stability by the E3 ubiquitin ligase CHIP.
  PLoS One, 4, e5949.  
19781641 Y.Li, L.Dunn, E.Greggio, B.Krumm, G.S.Jackson, M.R.Cookson, P.A.Lewis, and J.Deng (2009).
The R1441C mutation alters the folding properties of the ROC domain of LRRK2.
  Biochim Biophys Acta, 1792, 1194-1197.  
19104048 B.Krumm, X.Meng, Y.Li, Y.Xiang, and J.Deng (2008).
Structural basis for antagonism of human interleukin 18 by poxvirus interleukin 18-binding protein.
  Proc Natl Acad Sci U S A, 105, 20711-20715.
PDB code: 3f62
18397888 E.Greggio, I.Zambrano, A.Kaganovich, A.Beilina, J.M.Taymans, V.Daniëls, P.Lewis, S.Jain, J.Ding, A.Syed, K.J.Thomas, V.Baekelandt, and M.R.Cookson (2008).
The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation.
  J Biol Chem, 283, 16906-16914.  
18650931 K.Gotthardt, M.Weyand, A.Kortholt, P.J.Van Haastert, and A.Wittinghofer (2008).
Structure of the Roc-COR domain tandem of C. tepidum, a prokaryotic homologue of the human LRRK2 Parkinson kinase.
  EMBO J, 27, 2239-2249.
PDB codes: 3dpt 3dpu
19021752 M.J.Devine, and P.A.Lewis (2008).
Emerging pathways in genetic Parkinson's disease: tangles, Lewy bodies and LRRK2.
  FEBS J, 275, 5748-5757.  
18703517 W.N.van Egmond, A.Kortholt, K.Plak, L.Bosgraaf, S.Bosgraaf, I.Keizer-Gunnink, and P.J.van Haastert (2008).
Intramolecular activation mechanism of the Dictyostelium LRRK2 homolog Roco protein GbpC.
  J Biol Chem, 283, 30412-30420.  
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.

 

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