Parkinson's disease-associated mutations in the GTPase domain of LRRK2 impair its nucleotide-dependent conformational...

Area of Science:

• Molecular Biology
• Neuroscience
• Genetics

Background:

• Leucine-rich repeat kinase 2 (LRRK2) mutations are a leading genetic cause of familial Parkinson's disease (PD).
• A specific mutation, R1441H, was previously shown to reduce LRRK2's GTPase activity, locking it in an active conformation, but the underlying mechanism was unclear.

Purpose of the Study:

• To elucidate the mechanism by which PD-associated LRRK2 mutations alter the GTPase domain's conformation.
• To characterize the conformational dynamics of the Ras of complex protein (ROC) domain in LRRK2.

Main Methods:

• Investigated the monomer-dimer equilibrium of the LRRK2 ROC domain.
• Analyzed the effect of GDP and GTP binding on this equilibrium.
• Assessed the impact of Parkinson's disease-associated mutations at residue 1441 on ROC domain dynamics.

Main Results:

• The LRRK2 ROC domain exists in a dynamic equilibrium between monomer and dimer states, influenced by nucleotide binding.
• GDP binding favors dimerization, while GTP binding favors monomerization.
• Parkinson's disease-associated mutations at residue 1441 disrupt this equilibrium, favoring a monomeric, GTP-bound-like conformation.
• Residue Arg-1441 is crucial for regulating the conformational dynamics of the ROC domain.

Conclusions:

• PD-associated mutations at Arg-1441 of LRRK2 disrupt the normal monomer-dimer dynamics of the ROC domain.
• This disruption results in the GTPase domain being trapped in a constitutively active state.
• These findings provide critical insights into the molecular pathogenesis of LRRK2-linked Parkinson's disease.