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

• Published in: Biochimica et biophysica acta Vol. 1792; no. 12; pp. 1194 - 1197
• Main Authors: Li, Yongchao, Dunn, Laura, Greggio, Elisa, Krumm, Brian, Jackson, Graham S., Cookson, Mark R., Lewis, Patrick A., Deng, Junpeng
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2009; Elsevier
• Subjects: Calorimetry, Differential Scanning; Circular Dichroism; Differential scanning fluorimetry; GTPase; Guanosine Diphosphate - metabolism; Guanosine Triphosphate - metabolism; Humans; Immunoprecipitation; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; LRRK2; Macromolecular Substances; Mutation - genetics; Parkinson's disease; Protein Conformation; Protein Folding; Protein Serine-Threonine Kinases - chemistry; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein Structure, Tertiary; ras Proteins - genetics; ras Proteins - metabolism; ROCO protein; CD; GDP; GTP; Parkinson's disease; PD; DSF; LRRK2; ROC; ROCO protein; Differential scanning fluorimetry; GTPase; Circular dichroism; differential scanning fluorimetry; circular dichroism
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2009.09.010

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.