期刊
STRUCTURE
卷 28, 期 4, 页码 406-+出版社
CELL PRESS
DOI: 10.1016/j.str.2020.01.005
关键词
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资金
- Science Foundation Ireland Principal Investigator Awards [12/IA/1239]
- Michael J. Fox Foundation for Parkinson's research [6986]
- Michael J. Fox Foundation for Parkinson's research (Medical Research Council) [MC_UU_12016/2]
- Division of Signal Transduction Therapy Unit (Boehringer-Ingelheim)
- Division of Signal Transduction Therapy Unit (GlaxoSmithKline)
- Division of Signal Transduction Therapy Unit (Merck KGaA)
- Division of Newborn Medicine
- Program in Cellular and Molecular Medicine
- National Institute of General Medical Sciences from the NIH [P41 GM103403]
- NIH-ORIP HEI grant [S10 RR029205]
- DOE Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]
- Science Foundation Ireland (SFI) [12/IA/1239] Funding Source: Science Foundation Ireland (SFI)
- MRC [MC_UU_12016/2, MR/P00704X/1, MC_UU_00018/1, G0700656] Funding Source: UKRI
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 phosphoRab8a (pRab8a) in complex with the RH2 (RILP homology) 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, 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.
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