Each month, the open access team of the University of Groningen Library (UB) puts a recent open access article by UG authors in the spotlight. This publication is highlighted via social media and the library’s newsletter and website.

The article in the spotlight for the month of March 2025 is titled Intramolecular feedback regulation of the LRRK2 Roc G domain by a LRRK2 kinase-dependent mechanism, written by Bernd K. Gilsbach, Benjamin Riebenbauer, Giambattista Guaitoli, Christian Johannes Gloeckner (all from German Center for Neurodegenerative diseases (DZNE), Tübingen) and Franz Y. Ho, Xiaojuan Zhang and Arjan Kortholt (all from the Cell Biochemistry department at the Faculty of Science and Engineering). 

Abstract

The Parkinson’s disease (PD)-linked protein Leucine-Rich Repeat Kinase 2 (LRRK2) consists of seven domains, including a kinase and a Roc G domain. Despite the availability of several high-resolution structures, the dynamic regulation of its unique intramolecular domain stack is nevertheless still not well understood. By in-depth biochemical analysis, assessing the Michaelis–Menten kinetics of the Roc G domain, we have confirmed that LRRK2 has, similar to other Roco protein family members, a K_M value of LRRK2 that lies within the range of the physiological GTP concentrations within the cell. Furthermore, the R1441G PD variant located within a mutational hotspot in the Roc domain showed an increased catalytic efficiency. In contrast, the most common PD variant G2019S, located in the kinase domain, showed an increased K_M and reduced catalytic efficiency, suggesting a negative feedback mechanism from the kinase domain to the G domain. Autophosphorylation of the G1+2 residue (T1343) in the Roc P-loop motif is critical for this phosphoregulation of both the K_M and the k_cat values of the Roc-catalyzed GTP hydrolysis, most likely by changing the monomer–dimer equilibrium. The LRRK2 T1343A variant has a similar increased kinase activity in cells compared to G2019S and the double mutant T1343A/G2019S has no further increased activity, suggesting that T1343 is crucial for the negative feedback in the LRRK2 signaling cascade. Together, our data reveal a novel intramolecular feedback regulation of the LRRK2 Roc G domain by a LRRK2 kinase-dependent mechanism. Interestingly, PD mutants differently change the kinetics of the GTPase cycle, which might in part explain the difference in penetrance of these mutations in PD patients.

We asked corresponding author Arjan Kortholt a few questions about the article:

Could you explain in layman's terms what your research has discovered and what the possible consequences of your discovery are?

Mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) are the most common genetic cause of Parkinson’s disease. LRRK2 contains 2 enzymatic functions, GTPase (Roc domain) and kinase activity (kinase domain). All common PD mutations result in an increased kinase activity, therefore identifying small molecules that block LRRK2 is a major therapeutic target. However, the effect of PD-mutations on GTPase activity and the communication between the Roc and kinase domain was not studied in detail. In this paper we have revealed that the kinase domain phosphorylates the G-domain and thereby can switch the protein off. PD variants differently affect the GTPase, which might in part explain the difference in penetrance (risk) of these mutations in PD patients.

In 2023, publisher eLife introduced its innovative Publish-Review-Curate (PRC) model. In the PRC model, research manuscripts are shared publicly directly by the researcher - just like a preprint. The research then gets openly peer-reviewed by experts in the field. In the curation stage, research artifacts are organized, compiled, collected and enriched with summaries, judgments, metadata, etc. The key difference in this model is that publishing comes before - and not after - peer-review and curation, thus leaving the decision of ‘when’ to share research findings to the author(s), without gatekeeping from publishers and editors. How did you experience eLife’s publishing and peer review process, compared to traditional journals? 

In my opinion the new model functions well. Preprints are in general a good way to share data in a fast way.  You have claimed your work, other researchers can refer to it and it might help others to start new or finish their research. However, the whole process at eLife did take quite long. Furthermore, since they will not get an impact factor for 2025 and still charge a publication fee of €2500, I think they will get less submissions.

eLife provides an assessment with each publication (see eLife assessment explainer). Could you comment on the assessment given to your research (that it is a valuable article, but that the experimental evidence is currently incomplete)?

I completely agree with this assessment. To prove our new findings (see first question), additional experiments need to be done. We have discussed this in the paper and are currently performing the research.

Could you reflect on your experiences with open access and open science in general?

In my opinion all research should be published via open access. I think it is ridiculous that several high impact journals still ask an additional fee to make it immediately freely available. It is good to see that many researchers now publish their manuscript on preprint servers like bioRxiv and submit their raw data and protocols to repositories like Zenodo. 

Useful links

• An explanation of eLife’s Publish, Review, Curate (PRC) model

• bioRxiv, the preprint server for biology

• Zenodo is a general-purpose open repository. It allows researchers to deposit research papers, data sets, research software, reports, and any other research related digital artefacts

Citation

Gilsbach, B. K., Ho, F. Y., Riebenbauer, B., Zhang, X., Guaitoli, G., Kortholt, A., & Gloeckner, C. J. (2024). Intramolecular feedback regulation of the LRRK2 Roc G domain by a LRRK2 kinase-dependent mechanism. eLife, 12. https://doi.org/10.7554/elife.91083

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