PT  - JOURNAL ARTICLE
AU  - Waschbüsch, Dieter
AU  - Purlyte, Elena
AU  - Pal, Prosenjit
AU  - McGrath, Emma
AU  - Alessi, Dario R.
AU  - Khan, Amir R.
TI  - Structural basis for Rab8a GTPase recruitment of RILPL2 <em>via</em> LRRK2 phosphorylation of switch 2
AID  - 10.1101/739813
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 739813
4099  - http://biorxiv.org/content/early/2019/08/19/739813.short
4100  - http://biorxiv.org/content/early/2019/08/19/739813.full
AB  - 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 Parkinson’s 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 α-helical dimer that bridges two pRab8a molecules. The N-termini of the α-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.