• Register
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.


Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.


14-3-3 binding to LRRK2 is disrupted by multiple Parkinson's disease-associated mutations and regulates cytoplasmic localization.

LRRK2 (leucine-rich repeat protein kinase 2) is mutated in a significant number of Parkinson's disease patients, but still little is understood about how it is regulated or functions. In the present study we have demonstrated that 14-3-3 protein isoforms interact with LRRK2. Consistent with this, endogenous LRRK2 isolated from Swiss 3T3 cells or various mouse tissues is associated with endogenous 14-3-3 isoforms. We have established that 14-3-3 binding is mediated by phosphorylation of LRRK2 at two conserved residues (Ser910 and Ser935) located before the leucine-rich repeat domain. Our results suggests that mutation of Ser910 and/or Ser935 to disrupt 14-3-3 binding does not affect intrinsic protein kinase activity, but induces LRRK2 to accumulate within discrete cytoplasmic pools, perhaps resembling inclusion bodies. To investigate links between 14-3-3 binding and Parkinson's disease, we studied how 41 reported mutations of LRRK2 affected 14-3-3 binding and cellular localization. Strikingly, we found that five of the six most common pathogenic mutations (R1441C, R1441G, R1441H, Y1699C and I2020T) display markedly reduced phosphorylation of Ser910/Ser935 thereby disrupting interaction with 14-3-3. We have also demonstrated that Ser910/Ser935 phosphorylation and 14-3-3 binding to endogenous LRRK2 is significantly reduced in tissues of homozygous LRRK2(R1441C) knock-in mice. Consistent with 14-3-3 regulating localization, all of the common pathogenic mutations displaying reduced 14-3-3-binding accumulated within inclusion bodies. We also found that three of the 41 LRRK2 mutations analysed displayed elevated protein kinase activity (R1728H, ~2-fold; G2019S, ~3-fold; and T2031S, ~4-fold). These results provide the first evidence suggesting that 14-3-3 regulates LRRK2 and that disruption of the interaction of LRRK2 with 14-3-3 may be linked to Parkinson's disease.

Pubmed ID: 20642453


  • Nichols RJ
  • Dzamko N
  • Morrice NA
  • Campbell DG
  • Deak M
  • Ordureau A
  • Macartney T
  • Tong Y
  • Shen J
  • Prescott AR
  • Alessi DR


The Biochemical journal

Publication Data

September 15, 2010

Associated Grants

  • Agency: Medical Research Council, Id: G0700656
  • Agency: Medical Research Council, Id: MC_U127070193
  • Agency: Medical Research Council, Id:

Mesh Terms

  • 14-3-3 Proteins
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Brain
  • Cell Line
  • Cytoplasm
  • Green Fluorescent Proteins
  • Humans
  • Immunoprecipitation
  • Kidney
  • Mice
  • Mice, Knockout
  • Microscopy, Fluorescence
  • Molecular Sequence Data
  • Mutation
  • Parkinson Disease
  • Phosphorylation
  • Protein Binding
  • Protein-Serine-Threonine Kinases
  • Sequence Homology, Amino Acid
  • Serine
  • Spleen
  • Swiss 3T3 Cells