Conformation governs cellular behaviors of LRRK2 Parkinson's disease variants

Unlatching mutations in LRRK2 shift the kinase from autoinhibited to active conformations, linked to increased membrane localization and Rab substrate phosphorylation, with S935 phosphorylation as a conformation biomarker.

• Why it matters: Many PD-linked LRRK2 variants differ in activity, and structural studies have not reliably predicted which mutations preferentially unlatch and prime kinase function.
• What they did: The study defines a class of PD-associated unlatching mutations by their effects on LRRK2 conformation, using localization and phosphorylation readouts, including decreased LRRK2 S935 phosphorylation.
• The result: Unlatching mutants show increased membrane localization and decreased S935 phosphorylation, resolving mechanisms for variants like I2020T and enabling measurable readouts to identify LRRK2-driven disease.

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