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


Autoria(s): Li, Yongchao; Dunn, Laura; Greggio, Elisa; Krumm, Brian; Jackson, Graham S; Cookson, Mark R; Lewis, Patrick A; Deng, Junpeng
Data(s)

01/12/2009

Resumo

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.

Formato

text

Identificador

http://centaur.reading.ac.uk/30666/1/R1441C%20alters%20ROC%20domain%20folding%20Li%20et%20al%20BBArevisedmarked%20%282%29.pdf

Li, Y., Dunn, L., Greggio, E., Krumm, B., Jackson, G. S., Cookson, M. R., Lewis, P. A. <http://centaur.reading.ac.uk/view/creators/90005517.html> and Deng, J. (2009) The R1441C mutation alters the folding properties of the ROC domain of LRRK2. Biochimica Et Biophysica Acta-Molecular Basis of Disease, 1792 (12). pp. 1194-1197. ISSN 0925-4439 doi: 10.1016/j.bbadis.2009.09.010 <http://dx.doi.org/10.1016/j.bbadis.2009.09.010>

Idioma(s)

en

Publicador

Elsevier

Relação

http://centaur.reading.ac.uk/30666/

creatorInternal Lewis, Patrick A

10.1016/j.bbadis.2009.09.010

Tipo

Article

PeerReviewed