Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases.

ELife
Martin StegerMatthias Mann

Abstract

Mutations in Park8, encoding for the multidomain Leucine-rich repeat kinase 2 (LRRK2) protein, comprise the predominant genetic cause of Parkinson's disease (PD). G2019S, the most common amino acid substitution activates the kinase two- to threefold. This has motivated the development of LRRK2 kinase inhibitors; however, poor consensus on physiological LRRK2 substrates has hampered clinical development of such therapeutics. We employ a combination of phosphoproteomics, genetics, and pharmacology to unambiguously identify a subset of Rab GTPases as key LRRK2 substrates. LRRK2 directly phosphorylates these both in vivo and in vitro on an evolutionary conserved residue in the switch II domain. Pathogenic LRRK2 variants mapping to different functional domains increase phosphorylation of Rabs and this strongly decreases their affinity to regulatory proteins including Rab GDP dissociation inhibitors (GDIs). Our findings uncover a key class of bona-fide LRRK2 substrates and a novel regulatory mechanism of Rabs that connects them to PD.

References

Mar 23, 2002·Molecular and Cellular Biology·Giselle R WigginJ Simon C Arthur
Mar 7, 2003·Molecular Cell·Olena PylypenkoKirill Alexandrov
Jul 21, 2004·Current Opinion in Cell Biology·Miguel C Seabra, Christina Wasmeier
Mar 5, 2005·The Journal of Biological Chemistry·Suzanne R Pfeffer
Nov 5, 2005·Proceedings of the National Academy of Sciences of the United States of America·Andrew B WestTed M Dawson
Jan 16, 2007·Parkinsonism & Related Disorders·Matthew J FarrerRuey-Meei Wu
Dec 29, 2007·Proceedings of the National Academy of Sciences of the United States of America·Aaron D GitlerSusan Lindquist
Jan 1, 2009·Protein Expression and Purification·Nathalie BleimlingAymelt Itzen
Jun 6, 2009·Current Protocols in Cell Biology·Alexander Eberth, Mohammad Reza Ahmadian
Jun 16, 2009·Lancet·Andrew J LeesTamas Revesz
Jul 7, 2009·Biochemical and Biophysical Research Communications·Hong QingPatrick L McGeer
Jul 16, 2009·Nature Reviews. Molecular Cell Biology·Harald Stenmark
Jul 22, 2009·Current Opinion in Chemical Biology·Simone Lemeer, Albert J R Heck
Sep 11, 2009·The Biochemical Journal·R Jeremy NicholsDario R Alessi
Nov 17, 2009·Nature Genetics·Javier Simón-SánchezThomas Gasser
May 19, 2010·The Journal of Cell Biology·Nina C HubnerMatthias Mann
Jul 14, 2010·Nature Biotechnology·Parag Mallick, Bernhard Kuster
Oct 6, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·Agnès GardetDaniel K Podolsky
Jan 21, 2011·Physiological Reviews·Alex H Hutagalung, Peter J Novick
Jan 25, 2011·Journal of Proteome Research·Jürgen CoxMatthias Mann
Jan 29, 2011·Proceedings of the National Academy of Sciences of the United States of America·Christopher J WestlakePeter K Jackson
Apr 26, 2011·Journal of the Neurological Sciences·Lena F Burbulla, Rejko Krüger
Jun 23, 2011·The EMBO Journal·Viduth K ChauguleHelen Walden
Mar 17, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Yulan XiongValina L Dawson
Jun 28, 2012·Human Molecular Genetics·Tatiana D PapkovskaiaJ Mark Cooper
Aug 7, 2012·Bioorganic & Medicinal Chemistry Letters·Alastair D ReithNathanael S Gray
Sep 25, 2012·Neuron·Samer MattaPatrik Verstreken

❮ Previous
Next ❯

Citations

Mar 26, 2016·Cell Research·Kirby N Swatek, David Komander
Jun 14, 2016·Parkinson's Disease·Katharina E Rosenbusch, Arjan Kortholt
Jun 18, 2016·BioMed Research International·Dong Hwan HoWongi Seol
Jun 9, 2016·Nature Genetics·Han-Xiang DengTeepu Siddique
Jul 17, 2016·Proceedings of the National Academy of Sciences of the United States of America·Mark R Cookson
Aug 3, 2016·Proceedings of the National Academy of Sciences of the United States of America·Rebecca S LevinShaeri Mukherjee
Jan 6, 2017·Small GTPases·Matthias P Müller, Roger S Goody
Apr 21, 2017·Small GTPases·Swapnil Rohidas Shinde, Subbareddy Maddika
Apr 27, 2016·Current Biology : CB·Michael J Clague, Leila Rochin
Jan 25, 2017·Expert Opinion on Therapeutic Patents·Paul Galatsis
Mar 25, 2017·Cellular Signalling·Xiaosi LinTuanlao Wang
Apr 27, 2017·Expert Opinion on Therapeutic Targets·Sharon L Chan, Eng-King Tan
Feb 25, 2017·Current Opinion in Genetics & Development·Sandra TenreiroTiago Fleming Outeiro
Dec 16, 2016·Molecular Neurobiology·Garikoitz AzkonaRosario Sánchez-Pernaute
Dec 8, 2016·Journal of Cellular Physiology·Bor Luen Tang
Dec 14, 2016·Neurobiology of Disease·Laura A Volpicelli-Daley
Jun 14, 2017·Expert Opinion on Therapeutic Targets·Susanna CogoPatrick A Lewis
Apr 30, 2017·Human Molecular Genetics·Marian Blanca RamírezSabine Hilfiker
Feb 7, 2018·Stem Cells and Development·Scott C Vermilyea, Marina E Emborg
Mar 27, 2018·Human Molecular Genetics·Myung Jong KimDimitri Krainc
Mar 10, 2018·The Biochemical Journal·Alexia F KalogeropulouR Jeremy Nichols
May 9, 2018·Movement Disorders : Official Journal of the Movement Disorder Society·Manu Sharma
Oct 25, 2017·Cell and Tissue Research·Iva StojkovskaJoseph R Mazzulli
Nov 3, 2017·The Analyst·Justine V ArringtonW Andy Tao
Nov 10, 2017·Cell and Tissue Research·Maria Grazia Spillantini, Michel Goedert
Nov 24, 2017·Acta Neuropathologica Communications·Shijie WangAndrew B West
May 16, 2018·Proceedings of the National Academy of Sciences of the United States of America·Kwang Soo KimDavid S Park
Dec 14, 2017·Cell and Tissue Research·Melanie M CobbSteven Finkbeiner
Jan 10, 2018·Frontiers in Molecular Neuroscience·Laura CivieroElisa Greggio
Oct 25, 2017·Cell and Tissue Research·Marta Cherubini, Richard Wade-Martins
Jan 9, 2018·Cell and Tissue Research·Alice PricePatrick A Lewis
Feb 2, 2018·The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry·Tina De WitEvy Lobbestael
Sep 14, 2018·Proceedings of the National Academy of Sciences of the United States of America·Tomoya EguchiTakeshi Iwatsubo
Aug 9, 2018·American Journal of Physiology. Renal Physiology·Nathan J LanningBrendan D Looyenga

❮ Previous
Next ❯

Datasets Mentioned

BETA
PXD003071

Methods Mentioned

BETA
GTPase
GTPases
affinity-purification
immunoprecipitation
nucleotide exchange
ion-exchange chromatography
ion exchange chromatography
pull-down
affinity purification
gel filtration

Software Mentioned

R
GraphPad Prism
FL WinLab
AP
Cytoscape
MaxQuant
Mascot
GraphPad
Excel Prism
Xcalibur

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

Related Papers

European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies
C B Abdalla-CarvalhoM M G Pimentel
Archives of Neurology
Spiridon PapapetropoulosDeborah C Mash
© 2021 Meta ULC. All rights reserved