Structure
Volume 28, Issue 4, 7 April 2020, Pages 406-417.e6
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Article
Structural Basis for Rab8a Recruitment of RILPL2 via LRRK2 Phosphorylation of Switch 2

https://doi.org/10.1016/j.str.2020.01.005Get rights and content
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Highlights

  • Structure of LRRK2-phosphorylated Rab8a in complex with RH2 domain of effector RILPL2

  • Phosphothreonine in switch 2 of Rab8a recognized by an arginine from RILPL2

  • JIP3 and JIP4 have conserved arginine and bind to LRRK2-phosphorylated Rab10

  • Conserved mode of phospho-Rab recognition by RH2 domain of effector proteins

Summary

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.

Keywords

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

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