14-3-3 binding to LRRK2 is disrupted by multiple Parkinson's disease-associated mutations and regulates cytoplasmic localization
R. Jeremy Nichols,Nicolas Dzamko,Nicholas A. Morrice,David G. Campbell,Maria Deak,Alban Ordureau,Thomas Macartney,Youren Tong,Jie Shen,Alan R. Prescott,Dario R. Alessi +10 more
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TLDR
The results suggest 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.Abstract:
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.read more
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疟原虫var基因转换速率变化导致抗原变异[英]/Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A
TL;DR: PfPMP1)与感染红细胞、树突状组胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作�ly.
Journal ArticleDOI
Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases
Martin Steger,Francesca Tonelli,Genta Ito,Paul Davies,Matthias Trost,Melanie Vetter,Stefanie Wachter,Esben Lorentzen,Graham Duddy,Stephen S. Wilson,Marco A. S. Baptista,Brian K. Fiske,Matthew J. Fell,John A. Morrow,Alastair D. Reith,Dario R. Alessi,Matthias Mann +16 more
TL;DR: This work employs a combination of phosphoproteomics, genetics, and pharmacology to unambiguously identify a subset of Rab GTPases as key LRRK2 substrates and a novel regulatory mechanism of Rabs that connects them to PD.
Journal ArticleDOI
The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson’s disease
TL;DR: How mutations in a large complex gene — leucine-rich repeat kinase 2 (LRRK2) — affect protein function is discussed, and recent evidence that L RRK2 mutations affect pathways that involve other proteins that have been implicated in Parkinson's disease, specifically α-synuclein and tau.
Journal ArticleDOI
Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2
Xianming Deng,Nicolas Dzamko,Alan R. Prescott,Paul Davies,Qingsong Liu,Qingkai Yang,Jiing Dwan Lee,Matthew P. Patricelli,Tyzoon K. Nomanbhoy,Dario R. Alessi,Nathanael S. Gray +10 more
TL;DR: It is demonstrated that inhibition of LRRK2 induces dephosphorylation of Ser910/Ser935 and accumulation of L RRK2 within aggregate structures, which will serve as a versatile tool to pharmacologically interrogate LRRk2 biology and study its role in Parkinson’s disease.
Journal ArticleDOI
Recent advances in the genetics of Parkinson's disease.
TL;DR: Advances obtained from models of dominant mutations in α-synuclein and LRRK2 as well as recessive PINK1, parkin and DJ-1 mutations are reviewed, highlighting the likelihood of common mechanisms fundamental to the etiology of both familial and sporadic Parkinson's disease.
References
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疟原虫var基因转换速率变化导致抗原变异[英]/Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A
TL;DR: PfPMP1)与感染红细胞、树突状组胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作�ly.
Journal ArticleDOI
MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification.
Jiirgen Cox,Matthias Mann +1 more
TL;DR: MaxQuant, an integrated suite of algorithms specifically developed for high-resolution, quantitative MS data, detects peaks, isotope clusters and stable amino acid isotope–labeled (SILAC) peptide pairs as three-dimensional objects in m/z, elution time and signal intensity space and achieves mass accuracy in the p.p.b. range.
Journal ArticleDOI
Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology
Alexander Zimprich,Alexander Zimprich,Saskia Biskup,Petra Leitner,Peter Lichtner,Matthew J. Farrer,Sarah Lincoln,Jennifer M. Kachergus,Mary M. Hulihan,Ryan J. Uitti,Donald B. Calne,A. Jon Stoessl,Ronald F. Pfeiffer,Nadja Patenge,Iria Carballo Carbajal,Peter Vieregge,Friedrich Asmus,Bertram Müller-Myhsok,Dennis W. Dickson,Thomas Meitinger,Tim M. Strom,Zbigniew K. Wszolek,Thomas Gasser +22 more
TL;DR: High-resolution recombination mapping and candidate gene sequencing in 46 families found six disease-segregating mutations in a gene encoding a large, multifunctional protein, LRRK2 (leucine-rich repeat kinase 2), which may be central to the pathogenesis of several major neurodegenerative disorders associated with parkinsonism.
Journal ArticleDOI
Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's Disease
Coro Paisán-Ruiz,Shushant Jain,E. Whitney Evans,William P. Gilks,Javier Fernandez de Simon,Marcel P. van der Brug,Adolfo López de Munain,Silvia Aparicio,Angel Martı́nez Gil,Naheed L. Khan,Janel O. Johnson,Javier Ruiz Martínez,David Nicholl,Itxaso Marti Carrera,Amets Saénz Peňa,Rohan de Silva,Andrew J. Lees,Jose Felix Marti-Masso,Jordi Pérez-Tur,Nicholas W. Wood,Andrew B. Singleton +20 more
TL;DR: The cloning of a novel gene that contains missense mutations segregating with PARK8-linked PD in five families from England and Spain is described and this protein is named dardarin, derived from the Basque word dardara, meaning tremor, because of the tremor observed in PD.
Journal ArticleDOI
The structural basis for 14-3-3:phosphopeptide binding specificity.
Michael B. Yaffe,Katrin Rittinger,Stefano Volinia,Paul R. Caron,Alastair Aitken,Henrik Leffers,Steven J. Gamblin,Stephen J. Smerdon,Lewis C. Cantley,Lewis C. Cantley +9 more
TL;DR: It is shown that the 14-3-3 dimer binds tightly to single molecules containing tandem repeats of phosphoserine motifs, implicating bidentate association as a signaling mechanism with molecules such as Raf, BAD, and Cbl.
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