Evidence map›Paper›PMID 38570484›Full record

ArticleNPJ Parkinson's disease2024

RedOx regulation of LRRK2 kinase activity by active site cysteines.

Chiara R Trilling, Jui-Hung Weng, Pallavi Kaila Sharma, Viktoria Nolte, Jian Wu, Wen Ma, Daniela Boassa, Susan S Taylor, Friedrich W Herberg

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in NPJ Parkinson's disease, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
2.6field-weighted citation impact, top 10% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed, 7 citations in OpenAlex.

  1. Article
  2. Article
  3. Review
  4. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors at 3 institutions in 2 countries.

Chiara R TrillingDepartment of Biochemistry, University of Kassel, Kassel, Germany.ORCID http://orcid.org/0000-0002-3453-7688
Jui-Hung WengDepartment of Pharmacology, University of California, San Diego, CA, USA.ORCID http://orcid.org/0000-0002-0432-3515
Pallavi Kaila SharmaDepartment of Pharmacology, University of California, San Diego, CA, USA.ORCID http://orcid.org/0000-0003-2986-3515
Viktoria NolteDepartment of Biochemistry, University of Kassel, Kassel, Germany.ORCID http://orcid.org/0009-0003-6808-0123
Jian WuDepartment of Pharmacology, University of California, San Diego, CA, USA.ORCID http://orcid.org/0000-0002-8031-9462
Wen MaDepartment of Physics, University of Vermont, Burlington, VT, USA.ORCID http://orcid.org/0000-0002-1123-5273
Daniela BoassaNational Center for Microscopy and Imaging Research, University of California, San Diego, CA, USA.
Susan S TaylorDepartment of Pharmacology, University of California, San Diego, CA, USA.
Friedrich W HerbergDepartment of Biochemistry, University of Kassel, Kassel, Germany. herberg@uni-kassel.de.ORCID http://orcid.org/0000-0001-7117-7653
University of California San Diego · USUniversity of Kassel · DEUniversity of Vermont · US

Funding

THEORY OF BIOMOLECULAR DIFFUSIONR01GM031749 · NIGMS · UNIVERSITY OF HOUSTON · PI HUBER, GARY ALEXANDER, MCCAMMON, JAMES ANDREW · 1985 to 2022
$7.8M
Lessons Learned from PKA: Assembly of Dynamic Macromolecular SwitchesR35GM130389 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI SUSAN S. TAYLOR · 2019 to 2026
$5.7M
NIGMS NIH HHS R01 GM031749NIGMS NIH HHS R35 GM130389
6 · The paper itself

Abstract

Mutations of the human leucine-rich repeat kinase 2 (LRRK2) have been associated with both, idiopathic and familial Parkinson's disease (PD). Most of these pathogenic mutations are located in the kinase domain (KD) or GTPase domain of LRRK2. In this study we describe a mechanism in which protein kinase activity can be modulated by reversible oxidation or reduction, involving a unique pair of adjacent cysteines, the "CC" motif. Among all human protein kinases, only LRRK2 contains this "CC" motif (C2024 and C2025) in the Activation Segment (AS) of the kinase domain. In an approach combining site-directed mutagenesis, biochemical analyses, cell-based assays, and Gaussian accelerated Molecular Dynamics (GaMD) simulations we could attribute a role for each of those cysteines. We employed reducing and oxidizing agents with potential clinical relevance to investigate effects on kinase activity and microtubule docking. We find that each cysteine gives a distinct contribution: the first cysteine, C2024, is essential for LRRK2 protein kinase activity, while the adjacent cysteine, C2025, contributes significantly to redox sensitivity. Implementing thiolates (R-S

Identifiers

PMID38570484
PMCPMC10991482
OpenAlexW4393866830

What Socratic holds

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LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.