Structural and biochemical basis of ROC-dependent activation of LRRK2

Area of Science:

• Biochemistry
• Structural Biology
• Neuroscience

Background:

• Mutations in leucine-rich repeat kinase 2 (LRRK2) are a leading genetic cause of Parkinson's disease.
• The precise molecular mechanisms controlling LRRK2 activation are not fully understood.

Purpose of the Study:

• To elucidate the role of the Ras of complex proteins (ROC) GTPase domain in LRRK2 activation.
• To define the conformational dynamics governing LRRK2 kinase activity.

Main Methods:

• Cryo-electron microscopy (Cryo-EM) of full-length LRRK2.
• X-ray crystallography of the LRRK2 ROC domain.
• Structure-guided biochemical perturbations and disulfide engineering.

Main Results:

• LRRK2 exists in three intrinsic conformational states: autoinhibited, intermediate, and activated.
• The ROC domain exhibits inherent conformational plasticity influencing LRRK2 activation.
• A functional coupling between R1441 and switch II directly impacts GTPase activity, mimicking disease mutations.

Conclusions:

• The ROC domain acts as a dynamic regulator of LRRK2 activation through intramolecular conformational changes.
• Pathogenic LRRK2 mutations may promote aberrant kinase activity by disrupting this intrinsic activation pathway.