Home LiteratureArticle Details
PMID: 18650931 Published · ppublish English Journal Article

Structure of the Roc-COR domain tandem of C. tepidum, a prokaryotic homologue of the human LRRK2 Parkinson kinase.

The EMBO journal ·Vol. 27 ·No. 16 ·2008-08-20 ·Pages 2239-49

Gotthardt K, Weyand M, Kortholt A, Van Haastert PJ, Wittinghofer A

Abstract

Ras of complex proteins (Roc) belongs to the superfamily of Ras-related small G-proteins that always occurs in tandem with the C-terminal of Roc (COR) domain. This Roc-COR tandem is found in the bacterial and eukaryotic world. Its most prominent member is the leucine-rich repeat kinase LRRK2, which is mutated and activated in Parkinson patients. Here, we investigated biochemically and structurally the Roco protein from Chlorobium tepidum. We show that Roc is highly homologous to Ras, whereas the COR domain is a dimerisation device. The juxtaposition of the G-domains and mutational analysis suggest that the Roc GTPase reaction is stimulated and/or regulated by dimerisation in a nucleotide-dependent manner. The region most conserved between bacteria and man is the interface between Roc and COR, where single-point Parkinson mutations of the Roc and COR domains are in close proximity. The analogous mutations in C. tepidum Roc-COR decrease the GTPase reaction rate, most likely due to a modification of the interaction between the Roc and COR domains.

MeSH Terms
Bacterial Proteins/chemistry Chlorobium/enzymology Dimerization GTP Phosphohydrolases/metabolism Humans Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Models, Molecular Mutation/genetics Parkinson Disease/enzymology Prokaryotic Cells/enzymology Protein Serine-Threonine Kinases/chemistry Protein Structure, Secondary Protein Structure, Tertiary Sequence Homology, Amino Acid Trypsin/metabolism
Chemicals
Bacterial Proteins LRRK2 protein, human Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Protein Serine-Threonine Kinases Trypsin GTP Phosphohydrolases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Gotthardt Katja
Department of Structural Biology, Max-Planck-Institut for Molecular Physiology, Dortmund, Germany.
Weyand Michael
Kortholt Arjan
Van Haastert Peter J M
Wittinghofer Alfred
References (46)
46 references, click to expand
  1. Structural insight into filament formation by mammalian septins.
    Nature. 2007 Sep 20;449(7160):311-5 PMID: 17637674
  2. Refinement of macromolecular structures by the maximum-likelihood method.
    Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55 PMID: 15299926
  3. Mechanistic insight into the dominant mode of the Parkinson's disease-associated G2019S LRRK2 mutation.
    Hum Mol Genet. 2007 Sep 1;16(17):2031-9 PMID: 17584768
  4. How guanylate-binding proteins achieve assembly-stimulated processive cleavage of GTP to GMP.
    Nature. 2006 Mar 2;440(7080):101-4 PMID: 16511497
  5. Mechanism of association and reciprocal activation of two GTPases.
    PLoS Biol. 2004 Oct;2(10):e320 PMID: 15383838
  6. The structure of the TrmE GTP-binding protein and its implications for tRNA modification.
    EMBO J. 2005 Jan 12;24(1):23-33 PMID: 15616586
  7. GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease.
    Biochemistry. 2007 Feb 6;46(5):1380-8 PMID: 17260967
  8. The interferon-inducible GTPases.
    Annu Rev Cell Dev Biol. 2006;22:559-89 PMID: 16824009
  9. ras genes.
    Annu Rev Biochem. 1987;56:779-827 PMID: 3304147
  10. The guanine nucleotide-binding switch in three dimensions.
    Science. 2001 Nov 9;294(5545):1299-304 PMID: 11701921
  11. Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease.
    Lancet. 2005 Jan 29-Feb 4;365(9457):410-2 PMID: 15680455
  12. TBC-domain GAPs for Rab GTPases accelerate GTP hydrolysis by a dual-finger mechanism.
    Nature. 2006 Jul 20;442(7100):303-6 PMID: 16855591
  13. Substrate twinning activates the signal recognition particle and its receptor.
    Nature. 2004 Jan 15;427(6971):215-21 PMID: 14724630
  14. Genetics of Parkinson disease: paradigm shifts and future prospects.
    Nat Rev Genet. 2006 Apr;7(4):306-18 PMID: 16543934
  15. A common LRRK2 mutation in idiopathic Parkinson's disease.
    Lancet. 2005 Jan 29-Feb 4;365(9457):415-6 PMID: 15680457
  16. Roc, a Ras/GTPase domain in complex proteins.
    Biochim Biophys Acta. 2003 Dec 7;1643(1-3):5-10 PMID: 14654223
  17. Kinase activity of mutant LRRK2 mediates neuronal toxicity.
    Nat Neurosci. 2006 Oct;9(10):1231-3 PMID: 16980962
  18. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease.
    Neuron. 2004 Nov 18;44(4):595-600 PMID: 15541308
  19. The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation.
    J Biol Chem. 2008 Jun 13;283(24):16906-14 PMID: 18397888
  20. Monitoring the real-time kinetics of the hydrolysis reaction of guanine nucleotide-binding proteins.
    Biol Chem. 2005 Nov;386(11):1105-14 PMID: 16307476
  21. Structure of a GDP:AlF4 complex of the SRP GTPases Ffh and FtsY, and identification of a peripheral nucleotide interaction site.
    J Mol Biol. 2006 Jul 14;360(3):631-43 PMID: 16780874
  22. Identification of four candidate cGMP targets in Dictyostelium.
    Proc Natl Acad Sci U S A. 2002 May 14;99(10):6749-54 PMID: 12011437
  23. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.
    Neuron. 2004 Nov 18;44(4):601-7 PMID: 15541309
  24. 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. 2008 Feb 5;105(5):1499-504 PMID: 18230735
  25. 3D domain swapping: as domains continue to swap.
    Protein Sci. 2002 Jun;11(6):1285-99 PMID: 12021428
  26. Crystal structure of a small G protein in complex with the GTPase-activating protein rhoGAP.
    Nature. 1997 Aug 14;388(6643):693-7 PMID: 9262406
  27. Automated structure solution, density modification and model building.
    Acta Crystallogr D Biol Crystallogr. 2002 Nov;58(Pt 11):1937-40 PMID: 12393925
  28. Triphosphate structure of guanylate-binding protein 1 and implications for nucleotide binding and GTPase mechanism.
    EMBO J. 2000 Sep 1;19(17):4555-64 PMID: 10970849
  29. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration.
    Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18676-81 PMID: 16352719
  30. Structure of the guanine-nucleotide-binding domain of the Ha-ras oncogene product p21 in the triphosphate conformation.
    Nature. 1989 Sep 21;341(6239):209-14 PMID: 2476675
  31. Heterodimeric GTPase core of the SRP targeting complex.
    Science. 2004 Jan 16;303(5656):373-7 PMID: 14726591
  32. Structure of the small GTPase Rab27b shows an unexpected swapped dimer.
    Acta Crystallogr D Biol Crystallogr. 2007 Jul;63(Pt 7):769-79 PMID: 17582168
  33. Structure of an ABC transporter in complex with its binding protein.
    Nature. 2007 Mar 8;446(7132):213-6 PMID: 17322901
  34. Dimerisation-dependent GTPase reaction of MnmE: how potassium acts as GTPase-activating element.
    EMBO J. 2006 Jun 21;25(12):2940-51 PMID: 16763562
  35. Coot: model-building tools for molecular graphics.
    Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32 PMID: 15572765
  36. Mutations in LRRK2/dardarin associated with Parkinson disease are more toxic than equivalent mutations in the homologous kinase LRRK1.
    J Neurochem. 2007 Jul;102(1):93-102 PMID: 17394548
  37. Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity.
    Hum Mol Genet. 2007 Jan 15;16(2):223-32 PMID: 17200152
  38. Leucine-rich repeat kinase 2 (LRRK2)/PARK8 possesses GTPase activity that is altered in familial Parkinson's disease R1441C/G mutants.
    J Neurochem. 2007 Oct;103(1):238-47 PMID: 17623048
  39. The Parkinson's disease-associated protein, leucine-rich repeat kinase 2 (LRRK2), is an authentic GTPase that stimulates kinase activity.
    Exp Cell Res. 2007 Oct 1;313(16):3658-70 PMID: 17706965
  40. LRRK1 protein kinase activity is stimulated upon binding of GTP to its Roc domain.
    Cell Signal. 2006 Jun;18(6):910-20 PMID: 16243488
  41. Structural insights into HypB, a GTP-binding protein that regulates metal binding.
    J Biol Chem. 2006 Sep 15;281(37):27492-502 PMID: 16807243
  42. Kinase activity is required for the toxic effects of mutant LRRK2/dardarin.
    Neurobiol Dis. 2006 Aug;23(2):329-41 PMID: 16750377
  43. The R1441C mutation of LRRK2 disrupts GTP hydrolysis.
    Biochem Biophys Res Commun. 2007 Jun 8;357(3):668-71 PMID: 17442267
  44. Crystal structure of the GTPase-activating domain of human p120GAP and implications for the interaction with Ras.
    Nature. 1996 Dec 12;384(6609):591-6 PMID: 8955277
  45. The retinitis pigmentosa 2 gene product is a GTPase-activating protein for Arf-like 3.
    Nat Struct Mol Biol. 2008 Apr;15(4):373-80 PMID: 18376416
  46. LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson's disease mutants affect kinase activity.
    Biochem J. 2007 Jul 15;405(2):307-17 PMID: 17447891
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
1460-2075
DOI
10.1038/emboj.2008.150
Published
2008-08-20
Epub
2008-00-24
Pages
2239-49
Language
English
Region
England
NLM ID
8208664
PMCID
PMC2519104
Subset
IM
Databases
PDB
3PDT, 3PDU
Corrections
ErratumIn
-
External Links
PubMed source DOI: 10.1038/emboj.2008.150 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2