PXD003071-1

PXD003071 is an original dataset announced via ProteomeXchange.

Title	Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases
Description	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 three-fold. 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.
HostingRepository	PRIDE
AnnounceDate	2016-02-19
AnnouncementXML	Submission_2016-02-19_06:41:03.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Martin Steger
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606; scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue
Instrument	LTQ Orbitrap; Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2015-10-19 00:06:12	ID requested
⏵ 1	2016-02-19 06:41:04	announced

Steger M, Tonelli F, Ito G, Davies P, Trost M, Vetter M, Wachter S, Lorentzen E, Duddy G, Wilson S, Baptista MA, Fiske BK, Fell MJ, Morrow JA, Reith AD, Alessi DR, Mann M, Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases. Elife, 5():(2016) [pubmed]

submitter keyword: Phosphoproteomics, LRRK2, substrates, Rab GTPases

Matthias Mann
contact affiliation	Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried
contact email	mmann@biochem.mpg.de
lab head
Martin Steger
contact affiliation	Max Planck Institute of Biochemistry
contact email	steger@biochem.mpg.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/02/PXD003071

PRIDE project URI

• PRIDE
  1. PXD003071
     1. Label: PRIDE project
     2. Name: Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases