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Parkinson's disease-associated mutations in the GTPase domain of LRRK2 impair its nucleotide-dependent conformational dynamics.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2019 Apr 12; Vol. 294 (15), pp. 5907-5913. Date of Electronic Publication: 2019 Feb 22. - Publication Year :
- 2019
-
Abstract
- 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 Ras of complex protein (ROC) domain of LRRK2 exists in a dynamic dimer-monomer equilibrium that is oppositely driven by GDP and GTP binding. We also observed that the PD-associated mutations at residue 1441 impair this dynamic and shift the conformation of ROC to a GTP-bound-like monomeric conformation. Moreover, we show that residue Arg-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 monomer-dimer dynamics and thereby trap its GTPase domain in an activated state.
- Subjects :
- Amino Acid Substitution
Guanosine Diphosphate chemistry
Guanosine Diphosphate genetics
Guanosine Triphosphate chemistry
Guanosine Triphosphate genetics
HEK293 Cells
Humans
Protein Domains
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 chemistry
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 genetics
Mutation, Missense
Parkinson Disease enzymology
Parkinson Disease genetics
Protein Multimerization
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 294
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 30796162
- Full Text :
- https://doi.org/10.1074/jbc.RA119.007631