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  1. Article ; Online: CURTAIN-A unique web-based tool for exploration and sharing of MS-based proteomics data.

    Phung, Toan K / Berndsen, Kerryn / Shastry, Rosamund / Phan, Tran L C H B / Muqit, Miratul M K / Alessi, Dario R / Nirujogi, Raja S

    Proceedings of the National Academy of Sciences of the United States of America

    2024  Volume 121, Issue 7, Page(s) e2312676121

    Abstract: To facilitate analysis and sharing of mass spectrometry (MS)-based proteomics data, we created online tools called CURTAIN (https://curtain.proteo.info) and CURTAIN-PTM (https://curtainptm.proteo.info) with an accompanying series of video tutorials ( ... ...

    Abstract To facilitate analysis and sharing of mass spectrometry (MS)-based proteomics data, we created online tools called CURTAIN (https://curtain.proteo.info) and CURTAIN-PTM (https://curtainptm.proteo.info) with an accompanying series of video tutorials (https://www.youtube.com/@CURTAIN-me6hl). These are designed to enable non-MS experts to interactively peruse volcano plots and deconvolute primary experimental data so that replicates can be visualized in bar charts or violin plots and exported in publication-ready format. They also allow assessment of overall experimental quality by correlation matrix and profile plot analysis. After making a selection of protein "hits", the user can analyze known domain structure, AlphaFold predicted structure, reported interactors, relative expression as well as disease links. CURTAIN-PTM permits analysis of all identified PTM sites on protein(s) of interest with selected databases. CURTAIN-PTM also links with the Kinase Library to predict upstream kinases that may phosphorylate sites of interest. We provide examples of the utility of CURTAIN and CURTAIN-PTM in analyzing how targeted degradation of the PPM1H Rab phosphatase that counteracts the Parkinson's LRRK2 kinase impacts cellular protein levels and phosphorylation sites. We also reanalyzed a ubiquitylation dataset, characterizing the PINK1-Parkin pathway activation in primary neurons, revealing data of interest not highlighted previously. CURTAIN and CURTAIN-PTM are free to use and open source, enabling researchers to share and maximize the impact of their proteomics data. We advocate that MS data published in volcano plot format be reported containing a shareable CURTAIN weblink, thereby allowing readers to better analyze and exploit the data.
    MeSH term(s) Internet ; Mass Spectrometry ; Phosphorylation ; Protein Processing, Post-Translational ; Proteins/analysis ; Proteomics/methods ; Software
    Chemical Substances Proteins
    Language English
    Publishing date 2024-02-07
    Publishing country United States
    Document type Journal Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2312676121
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1148: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: Pathogenic LRRK2 control of primary cilia and Hedgehog signaling in neurons and astrocytes of mouse brain.

    Khan, Shahzad S / Sobu, Yuriko / Dhekne, Herschel S / Tonelli, Francesca / Berndsen, Kerryn / Alessi, Dario R / Pfeffer, Suzanne R

    eLife

    2021  Volume 10

    Abstract: Activating LRRK2 mutations cause Parkinson's disease, and pathogenic LRRK2 kinase interferes with ciliogenesis. Previously, we showed that cholinergic interneurons of the dorsal striatum lose their cilia in R1441C LRRK2 mutant mice (Dhekne et al., 2018). ...

    Abstract Activating LRRK2 mutations cause Parkinson's disease, and pathogenic LRRK2 kinase interferes with ciliogenesis. Previously, we showed that cholinergic interneurons of the dorsal striatum lose their cilia in R1441C LRRK2 mutant mice (Dhekne et al., 2018). Here, we show that cilia loss is seen as early as 10 weeks of age in these mice and also in two other mouse strains carrying the most common human G2019S LRRK2 mutation. Loss of the PPM1H phosphatase that is specific for LRRK2-phosphorylated Rab GTPases yields the same cilia loss phenotype seen in mice expressing pathogenic LRRK2 kinase, strongly supporting a connection between Rab GTPase phosphorylation and cilia loss. Moreover, astrocytes throughout the striatum show a ciliation defect in all LRRK2 and PPM1H mutant models examined. Hedgehog signaling requires cilia, and loss of cilia in LRRK2 mutant rodents correlates with dysregulation of Hedgehog signaling as monitored by in situ hybridization of
    MeSH term(s) Animals ; Astrocytes/physiology ; Brain ; Cilia/physiology ; Female ; Hedgehog Proteins/physiology ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism ; Male ; Mice ; Neurons/physiology ; Signal Transduction
    Chemical Substances Hedgehog Proteins ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (EC 2.7.11.1) ; Lrrk2 protein, mouse (EC 2.7.11.1)
    Language English
    Publishing date 2021-10-18
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.67900
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Structural basis for the specificity of PPM1H phosphatase for Rab GTPases.

    Waschbüsch, Dieter / Berndsen, Kerryn / Lis, Pawel / Knebel, Axel / Lam, Yuko Py / Alessi, Dario R / Khan, Amir R

    EMBO reports

    2021  Volume 22, Issue 11, Page(s) e52675

    Abstract: LRRK2 serine/threonine kinase is associated with inherited Parkinson's disease. LRRK2 phosphorylates a subset of Rab GTPases within their switch 2 motif to control their interactions with effectors. Recent work has shown that the metal-dependent protein ... ...

    Abstract LRRK2 serine/threonine kinase is associated with inherited Parkinson's disease. LRRK2 phosphorylates a subset of Rab GTPases within their switch 2 motif to control their interactions with effectors. Recent work has shown that the metal-dependent protein phosphatase PPM1H counteracts LRRK2 by dephosphorylating Rabs. PPM1H is highly selective for LRRK2 phosphorylated Rabs, and closely related PPM1J exhibits no activity towards substrates such as Rab8a phosphorylated at Thr72 (pThr72). Here, we have identified the molecular determinant of PPM1H specificity for Rabs. The crystal structure of PPM1H reveals a structurally conserved phosphatase fold that strikingly has evolved a 110-residue flap domain adjacent to the active site. The flap domain distantly resembles tudor domains that interact with histones in the context of epigenetics. Cellular assays, crosslinking and 3-D modelling suggest that the flap domain encodes the docking motif for phosphorylated Rabs. Consistent with this hypothesis, a PPM1J chimaera with the PPM1H flap domain dephosphorylates pThr72 of Rab8a both in vitro and in cellular assays. Therefore, PPM1H has acquired a Rab-specific interaction domain within a conserved phosphatase fold.
    MeSH term(s) Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism ; Phosphoprotein Phosphatases/genetics ; Phosphoprotein Phosphatases/metabolism ; Phosphorylation ; Protein Serine-Threonine Kinases ; rab GTP-Binding Proteins/genetics ; rab GTP-Binding Proteins/metabolism
    Chemical Substances Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Phosphoprotein Phosphatases (EC 3.1.3.16) ; rab GTP-Binding Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2021-09-28
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2020896-0
    ISSN 1469-3178 ; 1469-221X
    ISSN (online) 1469-3178
    ISSN 1469-221X
    DOI 10.15252/embr.202152675
    Database MEDical Literature Analysis and Retrieval System OnLINE

    Full text online

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5433: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 41: Show issues

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  4. Article ; Online: PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins.

    Berndsen, Kerryn / Lis, Pawel / Yeshaw, Wondwossen M / Wawro, Paulina S / Nirujogi, Raja S / Wightman, Melanie / Macartney, Thomas / Dorward, Mark / Knebel, Axel / Tonelli, Francesca / Pfeffer, Suzanne R / Alessi, Dario R

    eLife

    2019  Volume 8

    Abstract: Mutations that activate LRRK2 protein kinase cause Parkinson's disease. LRRK2 phosphorylates a subset of Rab GTPases within their Switch-II motif controlling interaction with effectors. An siRNA screen of all human protein phosphatases revealed that a ... ...

    Abstract Mutations that activate LRRK2 protein kinase cause Parkinson's disease. LRRK2 phosphorylates a subset of Rab GTPases within their Switch-II motif controlling interaction with effectors. An siRNA screen of all human protein phosphatases revealed that a poorly studied protein phosphatase, PPM1H, counteracts LRRK2 signaling by specifically dephosphorylating Rab proteins. PPM1H knockout increased endogenous Rab phosphorylation and inhibited Rab dephosphorylation in human A549 cells. Overexpression of PPM1H suppressed LRRK2-mediated Rab phosphorylation. PPM1H also efficiently and directly dephosphorylated Rab8A in biochemical studies. A "substrate-trapping" PPM1H mutant (Asp288Ala) binds with high affinity to endogenous, LRRK2-phosphorylated Rab proteins, thereby blocking dephosphorylation seen upon addition of LRRK2 inhibitors. PPM1H is localized to the Golgi and its knockdown suppresses primary cilia formation, similar to pathogenic LRRK2. Thus, PPM1H acts as a key modulator of LRRK2 signaling by controlling dephosphorylation of Rab proteins. PPM1H activity enhancers could offer a new therapeutic approach to prevent or treat Parkinson's disease.
    MeSH term(s) Humans ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism ; Phosphoprotein Phosphatases/metabolism ; Phosphorylation ; RNA, Small Interfering/genetics ; Signal Transduction ; rab GTP-Binding Proteins/genetics ; rab GTP-Binding Proteins/metabolism
    Chemical Substances RNA, Small Interfering ; LRRK2 protein, human (EC 2.7.11.1) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (EC 2.7.11.1) ; PPM1H protein, human (EC 3.1.3.16) ; Phosphoprotein Phosphatases (EC 3.1.3.16) ; rab GTP-Binding Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2019-10-30
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.50416
    Database MEDical Literature Analysis and Retrieval System OnLINE

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