Structural Basis for Rab8a Recruitment of RILPL2 via LRRK2 Phosphorylation of Switch 2

Dieter Waschbüsch, Elena Purlyte, Prosenjit Pal, Emma McGrath, Dario R. Alessi, Amir R. Khan (Lead / Corresponding author)

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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 leucinerich 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 this 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 a-helical dimer that bridges two pRab8a molecules. The N-termini of the a-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.
Original languageEnglish
Pages (from-to)406-417.e1-e6
Number of pages19
Early online date3 Feb 2020
Publication statusPublished - 7 Apr 2020



  • effector
  • LRRK2 kinase
  • membrane trafficking
  • Rab8a GTPase
  • RILP-like protein 2

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