Parkinson's disease-associated mutations in the GTPase domain of LRRK2 impair its nucleotide-dependent conformational dynamics [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 616.8 Diseases of nervous system and mental disorders
• Thông tin xuất bản: Arlington, Va. : Oak Ridge, Tenn. : National Science Foundation (U.S.) ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2019
• Mô tả vật lý: Size: p. 5907-5913 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260098
• Chủ đề: 1. 60 applied life sciences; 2. Conformational dynamics; 3. Disease mutation; 4. Enzyme activation; 5. Gtpase; 6. Kinase; 7. Leucine-rich repeat kinase 2 (lrrk2); 8. Neurodegeneration; 9. Parkinson's disease; 10. Ras of complex proteins (roc)

Tóm tắt

Mutation in Leucine Rich Repeat Kinase 2 (LRRK2) is a common cause of familial Parkinson's disease (PD). Recently, we showed that a disease-associated mutation R1441H rendered the GTPase domain of LRRK2 catalytically less active and thereby trapping it in a more persistently "on" conformation. However, the mechanism involved and characteristics of this "on" conformation remained unknown. Here, we report that the ROC domain of LRRK2 exists in a dynamic dimermonomer equilibrium that is oppositely driven by GDP and GTP binding. We also observed that the diseaseassociated mutations at residue 1441 impair this dynamic and shift the conformation of ROC to a GTPbound- like monomeric conformation. Moreover, we show that residue arginine 1441 is critical for regulating the conformational dynamics of ROC. In summary, our results reveal that the PD-associated substitutions at Arg-1441 of LRRK2 alter monomerdimer dynamics and thereby trap its GTPase domain in an activated state.