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The R1441C mutation alters the folding properties of the ROC domain of LRRK2

Li, YC; Dunn, L; Greggio, E; Krumm, B; Jackson, GS; Cookson, MR; Lewis, PA; (2009) The R1441C mutation alters the folding properties of the ROC domain of LRRK2. BBA-MOL BASIS DIS , 1792 (12) 1194 - 1197. 10.1016/j.bbadis.2009.09.010.

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Abstract

LRRK2 is a 250 kDa multidomain protein, mutations in which cause familial Parkinson's disease. Previously, we have demonstrated that the R1441C mutation in the ROC domain decreases GTPase activity. Here we show that the R1441C alters the folding properties of the ROC domain, lowering its thermodynamic stability. Similar to small GTPases, binding of different guanosine nucleotides alters the stability of the ROC domain, suggesting that there is an alteration in conformation dependent on GDP or GTP occupying the active site. GTP/GDP bound state also alters the self-interaction of the ROC domain, accentuating the impact of the R1441C mutation on this property. These data suggest a mechanism whereby the R1441C mutation can reduce the GTPase activity of LRRK2, and highlights the possibility of targeting the stability of the ROC domain as a therapeutic avenue in LRRK2 disease. (C) 2009 Elsevier B.V. All rights reserved.

Type: Article
Title: The R1441C mutation alters the folding properties of the ROC domain of LRRK2
DOI: 10.1016/j.bbadis.2009.09.010
Keywords: LRRK2, ROCO protein, GTPase, Parkinson's disease, Differential scanning fluorimetry, Circular dichroism, DISEASE-ASSOCIATED MUTATIONS, FAMILIAL PARKINSONS-DISEASE, PROTEIN-KINASE ACTIVITY, LEUCINE-RICH-REPEAT-KINASE-2 LRRK2, NEURONAL TOXICITY, GTP-BINDING, GENE, MUTANTS
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: http://discovery.ucl.ac.uk/id/eprint/123062
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