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bioRxiv · 10.1101/739813

Structural basis for Rab8a GTPase recruitment of RILPL2 via LRRK2 phosphorylation of switch 2

Khan, A. R.·Alessi, D. R.·Waschbusch, D.·Purlyte, E.·Pal, P.·McGrath, E.
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Abstract

Rab8a GTPase is associated with the dynamic regulation of membrane protrusions in polarized cells. Rab8a is one of several Rab-family GTPases that are substrates of leucine-rich repeat kinase 2 (LRRK2), a serine/threonine kinase that is linked to inherited Parkinsons disease. Rab8a is phosphorylated at T72 (pT72) in its switch 2 helix and the post-translational modification facilitates phospho-Rab8a (pRab8a) interactions with RILPL2, which subsequently regulates ciliogenesis. Here we report the crystal structure of pRab8a in complex with the phospho-Rab binding domain of RILPL2. The complex is a heterotetramer with RILPL2 forming a central -helical dimer that bridges two pRab8a molecules. The N-termini of the -helices cross over to form an X-shaped cap (X-cap) that enables electrostatic interactions between Arg residues from RILPL2 and the phosphate moiety from pT72. RILPL2 residues in the X-cap that are critical for pRab8a binding are conserved in the RILP family of effector proteins. We find that JIP3 and JIP4 also interact specifically with LRRK2-phosphorylated Rab10, suggesting a general mode of recognition for phosphorylated Rab GTPases by phospho-specific effectors.

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Khan, A. R., Alessi, D. R., Waschbusch, D., Purlyte, E., Pal, P., McGrath, E.. 2019-08-19. Structural basis for Rab8a GTPase recruitment of RILPL2 via LRRK2 phosphorylation of switch 2. https://doi.org/10.1101/739813

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