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)

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
52 Downloads (Pure)

Abstract

Rab8a is associated with the dynamic regulation of membrane protrusions in polarized cells. Rab8a is one of several Rab GTPases that are substrates of leucine-rich repeat kinase 2 (LRRK2), a serine/threonine kinase that is linked to Parkinson's disease. Rab8a is phosphorylated at T72 (pT72) in its switch 2 helix and recruits the phospho-specific effector RILPL2, which subsequently regulates ciliogenesis. Here, we report the crystal structure of phospho-Rab8a (pRab8a) in complex with the RH2 (RILP homology) 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, forming an X-shaped cap (X-cap) that orients Arg residues from RILPL2 toward pT72. X-cap residues critical for pRab8a binding are conserved in JIP3 and JIP4, which also interact with LRRK2-phosphorylated Rab10. We propose a general mode of recognition for phosphorylated Rab GTPases by this family of phospho-specific effectors.

Original languageEnglish
Pages (from-to)406-417.e6
Number of pages19
JournalStructure
Volume28
Issue number4
Early online date3 Feb 2020
DOIs
Publication statusPublished - 7 Apr 2020

Keywords

  • JNK-interacting protein 3 and 4
  • LRRK2 kinase
  • RILP-like protein 2
  • Rab8a GTPase
  • effector
  • membrane trafficking

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