arhgef7 (beta-pix) acts as guanine nucleotide exchange factor for leucine-rich repeat kinase 2arhgef7(beta-pix)作为鸟嘌呤核苷酸交换因子富亮氨酸重复激酶2.pdfVIP

ARHGEF7 (BETA-PIX) Acts as Guanine Nucleotide Exchange Factor for Leucine-Rich Repeat Kinase 2 1 2,3 4 5 Karina Haebig , Christian Johannes Gloeckner , Marta Garcia Miralles , Frank Gillardon , Claudia 4 1 2,3 1,4 1 Schulte , Olaf Riess , Marius Ueffing , Saskia Biskup *, Michael Bonin * 1 Institute of Human Genetics, Department of Medical Genetics, University of Tuebingen, Tuebingen, Germany, 2 Department of Protein Science, Helmholtz-Zentrum ¨ Munchen, Munich, Germany, 3 Center for Ophthalmology, Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany, 4 Hertie Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases, University of Tuebingen, Tuebingen, Germany, 5 Boehringer-Ingelheim Pharma GmbH Co. KG, CNS Research, Biberach an der Riss, Germany Abstract Background: Mutations within the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of familial and sporadic Parkinson’s disease. The multidomain protein LRRK2 exhibits overall low GTPase and kinase activity in vitro. Methodology/Principal Findings: Here, we show that the rho guanine nucleotide exchange factor ARHGEF7 and the small GTPase CDC42 are interacting with LRRK2 in vitro and in vivo. GTPase activity of full-length LRRK2 increases in the presence of recombinant ARHGEF7. Interestingly, LRRK2 phosphorylates ARHGEF7 in vitro at previously unknown phosphorylation sites. We provide evidence that ARHGEF7 might act as a guanine nucleotide exchange factor for LRRK2 and that R1441C mutant LRRK2 with reduced GTP hydrolysis activity also shows reduced binding to ARHGEF7. Conclusi