{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T10:38:40Z","timestamp":1787567920930,"version":"build-2736575974"},"reference-count":61,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T00:00:00Z","timestamp":1734566400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T00:00:00Z","timestamp":1734566400000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T00:00:00Z","timestamp":1734566400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","award":["8068.04"],"award-info":[{"award-number":["8068.04"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>\n                    The Parkinson\u2019s 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\u2013Menten kinetics of the Roc G domain, we have confirmed that LRRK2 has, similar to other Roco protein family members, a K\n                    <jats:sub>M<\/jats:sub>\n                    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\n                    <jats:sub>M<\/jats:sub>\n                    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\n                    <jats:sub>M<\/jats:sub>\n                    and the k\n                    <jats:sub>cat<\/jats:sub>\n                    values of the Roc-catalyzed GTP hydrolysis, most likely by changing the monomer\u2013dimer 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.\n                  <\/jats:p>","DOI":"10.7554\/elife.91083","type":"journal-article","created":{"date-parts":[[2023,11,28]],"date-time":"2023-11-28T11:13:02Z","timestamp":1701169982000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.91083","source":"Crossref","is-referenced-by-count":5,"title":["Intramolecular feedback regulation of the LRRK2 Roc G domain by a LRRK2 kinase-dependent mechanism"],"prefix":"10.7554","volume":"12","author":[{"given":"Bernd K","family":"Gilsbach","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043j0f473","id-type":"ROR","asserted-by":"publisher"}],"name":"German Center for Neurodegenerative diseases (DZNE)","place":["T\u00fcbingen, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Franz Y","family":"Ho","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/012p63287","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Cell Biochemistry, University of Groningen","place":["Groningen, Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Benjamin","family":"Riebenbauer","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043j0f473","id-type":"ROR","asserted-by":"publisher"}],"name":"German Center for Neurodegenerative diseases (DZNE)","place":["T\u00fcbingen, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Xiaojuan","family":"Zhang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/012p63287","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Cell Biochemistry, University of Groningen","place":["Groningen, Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Giambattista","family":"Guaitoli","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043j0f473","id-type":"ROR","asserted-by":"publisher"}],"name":"German Center for Neurodegenerative diseases (DZNE)","place":["T\u00fcbingen, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8174-6397","authenticated-orcid":true,"given":"Arjan","family":"Kortholt","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/012p63287","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Cell Biochemistry, University of Groningen","place":["Groningen, Netherlands"]},{"id":[{"id":"https:\/\/ror.org\/04fjtte88","id-type":"ROR","asserted-by":"publisher"}],"name":"YETEM-Innovative Technologies Application and Research Centre, Suleyman Demirel University West Campus","place":["Isparta, Turkey"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"corresponding-author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6494-6944","authenticated-orcid":true,"given":"Christian Johannes","family":"Gloeckner","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043j0f473","id-type":"ROR","asserted-by":"publisher"}],"name":"German Center for Neurodegenerative diseases (DZNE)","place":["T\u00fcbingen, Germany"]},{"id":[{"id":"https:\/\/ror.org\/03a1kwz48","id-type":"ROR","asserted-by":"publisher"}],"name":"Core Facility for Medical Bioanalytics, Institute for Ophthalmic Research, Center for Ophthalmology, University of T\u00fcbingen","place":["T\u00fcbingen, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"corresponding-author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"4374","published-online":{"date-parts":[[2024,12,19]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","type":"journal-article","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"4535","DOI":"10.1021\/bi962556y","type":"journal-article","article-title":"Individual rate constants for the interaction of Ras proteins with GTPase-activating proteins determined by fluorescence spectroscopy","volume":"36","author":"Ahmadian","year":"1997","journal-title":"Biochemistry"},{"key":"bib3","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.00193","type":"journal-article","article-title":"Leucine rich repeat kinase 2 and Innate Immunity","volume":"14","author":"Ahmadi Rastegar","year":"2020","journal-title":"Frontiers in Neuroscience"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1146\/annurev-biochem-030122-051144","type":"journal-article","article-title":"Leucine-rich repeat kinases","volume":"93","author":"Alessi","year":"2024","journal-title":"Annual Review of Biochemistry"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"5511","DOI":"10.1021\/bi100157u","type":"journal-article","article-title":"Membrane localization of LRRK2 is associated with increased formation of the highly active LRRK2 dimer and changes in its phosphorylation","volume":"49","author":"Berger","year":"2010","journal-title":"Biochemistry"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"1140","DOI":"10.1093\/hmg\/dds522","type":"journal-article","article-title":"GTPase activity regulates kinase activity and cellular phenotypes of Parkinson\u2019s disease-associated LRRK2","volume":"22","author":"Biosa","year":"2013","journal-title":"Human Molecular Genetics"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"2069","DOI":"10.4161\/cc.10.13.16245","type":"journal-article","article-title":"Biology using engineering tools: the negative feedback amplifier","volume":"10","author":"Birtwistle","year":"2011","journal-title":"Cell Cycle"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/s0076-6879(95)55020-8","type":"journal-article","article-title":"Intrinsic and gtpase-activating protein-stimulated ras gtpase assays","volume":"255","author":"Bollag","year":"1995","journal-title":"Methods in Enzymology"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.ceb.2019.03.009","type":"journal-article","article-title":"The role of Rab GTPases in the pathobiology of Parkinson\u2019 disease","volume":"59","author":"Bonet-Ponce","year":"2019","journal-title":"Current Opinion in Cell Biology"},{"key":"bib10","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-05760-9","type":"journal-article","article-title":"The LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions","volume":"7","author":"Carrion","year":"2017","journal-title":"Scientific Reports"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1038\/s41586-020-2673-2","type":"journal-article","article-title":"Structure of LRRK2 in Parkinson\u2019s disease and model for microtubule interaction","volume":"588","author":"Deniston","year":"2020","journal-title":"Nature"},{"key":"bib12","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01103-4","type":"journal-article","article-title":"A homologue of the Parkinson\u2019s disease-associated protein LRRK2 undergoes A monomer-dimer transition during GTP turnover","volume":"8","author":"Deyaert","year":"2017","journal-title":"Nature Communications"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1016\/j.bbrc.2003.10.171","type":"journal-article","article-title":"Tyrosine phosphorylation of the Rab24 GTPase in cultured mammalian cells","volume":"312","author":"Ding","year":"2003","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.3233\/JPD-202138","type":"journal-article","article-title":"LRRK2 and the endolysosomal system in Parkinson\u2019s Disease","volume":"10","author":"Erb","year":"2020","journal-title":"Journal of Parkinson\u2019s Disease"},{"key":"bib15","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.94503","type":"journal-article","article-title":"Structural insights into the GTP-driven monomerization and activation of a bacterial LRRK2 homolog using allosteric nanobodies","volume":"13","author":"Galicia","year":"2024","journal-title":"eLife"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1093\/hmg\/ddi439","type":"journal-article","article-title":"The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity","volume":"15","author":"Gloeckner","year":"2006","journal-title":"Human Molecular Genetics"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"4228","DOI":"10.1002\/pmic.200700038","type":"journal-article","article-title":"A novel tandem affinity purification strategy for the efficient isolation and characterisation of native protein complexes","volume":"7","author":"Gloeckner","year":"2007","journal-title":"Proteomics"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"1738","DOI":"10.1021\/pr9008578","type":"journal-article","article-title":"Phosphopeptide analysis reveals two discrete clusters of phosphorylation in the N-terminus and the Roc domain of the Parkinson-disease associated protein kinase LRRK2","volume":"9","author":"Gloeckner","year":"2010","journal-title":"Journal of Proteome Research"},{"key":"bib19","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.00485","type":"journal-article","article-title":"Guilt-by-association - functional insights gained from studying the LRRK2 Interactome","volume":"14","author":"Gloeckner","year":"2020","journal-title":"Frontiers in Neuroscience"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"4157","DOI":"10.1083\/jcb.201902184","type":"journal-article","article-title":"Membrane association but not identity is required for LRRK2 activation and phosphorylation of Rab GTPases","volume":"218","author":"Gomez","year":"2019","journal-title":"The Journal of Cell Biology"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"2239","DOI":"10.1038\/emboj.2008.150","type":"journal-article","article-title":"Structure of the Roc-COR domain tandem of C. tepidum, a prokaryotic homologue of the human LRRK2 Parkinson kinase","volume":"27","author":"Gotthardt","year":"2008","journal-title":"The EMBO Journal"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1016\/j.bbrc.2009.08.163","type":"journal-article","article-title":"The Parkinson\u2019s disease kinase LRRK2 autophosphorylates its GTPase domain at multiple sites","volume":"389","author":"Greggio","year":"2009","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"E4357","DOI":"10.1073\/pnas.1523708113","type":"journal-article","article-title":"Structural model of the dimeric Parkinson\u2019s protein LRRK2 reveals a compact architecture involving distant interdomain contacts","volume":"113","author":"Guaitoli","year":"2016","journal-title":"PNAS"},{"key":"bib24","doi-asserted-by":"publisher","DOI":"10.1101\/2023.08.11.549911","type":"preprint","article-title":"Biophysical Analysis Reveals Autophosphorylation as an Important Negative Regulator of LRRK2 Dimerization","volume-title":"bioRxiv","author":"Guaitoli","year":"2023"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"1456","DOI":"10.1212\/01.wnl.0000304044.22253.03","type":"journal-article","article-title":"Lrrk2 R1441C parkinsonism is clinically similar to sporadic Parkinson disease","volume":"70","author":"Haugarvoll","year":"2008","journal-title":"Neurology"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"2326","DOI":"10.1021\/acschembio.1c00487","type":"journal-article","article-title":"Allosteric Inhibition of Parkinson\u2019s-Linked LRRK2 by constrained peptides","volume":"16","author":"Helton","year":"2021","journal-title":"ACS Chemical Biology"},{"key":"bib27","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/7917128","type":"journal-article","article-title":"G2385R and I2020T mutations increase LRRK2 GTPase activity","volume":"2016","author":"Ho","year":"2016","journal-title":"BioMed Research International"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"1380","DOI":"10.1021\/bi061960m","type":"journal-article","article-title":"GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson\u2019s disease","volume":"46","author":"Ito","year":"2007","journal-title":"Biochemistry"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1042\/BJ20070209","type":"journal-article","article-title":"LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson\u2019s disease mutants affect kinase activity","volume":"405","author":"Jaleel","year":"2007","journal-title":"The Biochemical Journal"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"L41","DOI":"10.1016\/j.bpj.2012.04.046","type":"journal-article","article-title":"Number and brightness analysis of LRRK2 oligomerization in live cells","volume":"102","author":"James","year":"2012","journal-title":"Biophysical Journal"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"1759","DOI":"10.1042\/BCJ20220161","type":"journal-article","article-title":"Impact of 100 LRRK2 variants linked to Parkinson\u2019s disease on kinase activity and microtubule binding","volume":"479","author":"Kalogeropulou","year":"2022","journal-title":"The Biochemical Journal"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1111\/j.1432-1033.1983.tb07643.x","type":"journal-article","article-title":"Meaningful relationships: the regulation of the Ras\/Raf\/MEK\/ERK pathway by protein interactions","volume":"351 Pt 2","author":"Kolch","year":"2000","journal-title":"The Biochemical Journal"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1016\/j.bbrc.2007.04.006","type":"journal-article","article-title":"The R1441C mutation of LRRK2 disrupts GTP hydrolysis","volume":"357","author":"Lewis","year":"2007","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"2008","DOI":"10.1021\/bi901851y","type":"journal-article","article-title":"Kinetic mechanistic studies of wild-type leucine-rich repeat kinase2: characterization of the kinase and GTPase activities","volume":"49","author":"Liu","year":"2010","journal-title":"Biochemistry"},{"key":"bib35","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1096\/fj.15-277095","type":"journal-article","article-title":"LRRK2 autophosphorylation enhances its GTPase activity","volume":"30","author":"Liu","year":"2016","journal-title":"FASEB Journal"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1016\/j.bbapap.2016.12.001","type":"journal-article","article-title":"The dual enzyme LRRK2 hydrolyzes GTP in both its GTPase and kinase domains in vitro","volume":"1865","author":"Liu","year":"2017","journal-title":"Biochimica et Biophysica Acta. Proteins and Proteomics"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"3103","DOI":"10.1096\/fj.08-111310","type":"journal-article","article-title":"The Roco protein family: a functional perspective","volume":"22","author":"Mar\u00edn","year":"2008","journal-title":"FASEB Journal"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"2934","DOI":"10.1038\/sj.onc.1210957","type":"journal-article","article-title":"Constitutive activation of the Raf-MAPK pathway causes negative feedback inhibition of Ras-PI3K-AKT and cellular arrest through the EphA2 receptor","volume":"27","author":"Menges","year":"2008","journal-title":"Oncogene"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"1086","DOI":"10.1042\/BST20120088","type":"journal-article","article-title":"Analysis of LRRK2 accessory repeat domains: prediction of repeat length, number and sites of Parkinson\u2019s disease mutations","volume":"40","author":"Mills","year":"2012","journal-title":"Biochemical Society Transactions"},{"key":"bib40","doi-asserted-by":"publisher","first-page":"24000","DOI":"10.1074\/jbc.M113.470625","type":"journal-article","article-title":"The Legionella pneumophila GTPase activating protein LepB accelerates Rab1 deactivation by a non-canonical hydrolytic mechanism","volume":"288","author":"Mishra","year":"2013","journal-title":"The Journal of Biological Chemistry"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"3519","DOI":"10.1016\/j.cell.2021.05.004","type":"journal-article","article-title":"Structural analysis of the full-length human LRRK2","volume":"184","author":"Myasnikov","year":"2021","journal-title":"Cell"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1016\/j.neuron.2004.10.023","type":"journal-article","article-title":"Cloning of the gene containing mutations that cause PARK8-linked Parkinson\u2019s disease","volume":"44","author":"Pais\u00e1n-Ru\u00edz","year":"2004","journal-title":"Neuron"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"1971","DOI":"10.1021\/acschemneuro.3c00259","type":"journal-article","article-title":"Doubly constrained C-terminal of Roc (COR) domain-derived peptides inhibit leucine-rich repeat kinase 2 (LRRK2) dimerization","volume":"14","author":"Pathak","year":"2023","journal-title":"ACS Chemical Neuroscience"},{"key":"bib44","doi-asserted-by":"publisher","DOI":"10.1002\/0471142727.mb1606s28","type":"journal-article","article-title":"Expression and purification of maltose\u2010binding protein fusions","volume":"28","author":"Riggs","year":"1994","journal-title":"Current Protocols in Molecular Biology"},{"key":"bib45","doi-asserted-by":"publisher","first-page":"4201","DOI":"10.1093\/hmg\/ddu138","type":"journal-article","article-title":"Membrane recruitment of endogenous LRRK2 precedes its potent regulation of autophagy","volume":"23","author":"Schapansky","year":"2014","journal-title":"Human Molecular Genetics"},{"key":"bib46","doi-asserted-by":"publisher","first-page":"1308","DOI":"10.1038\/ng.487","type":"journal-article","article-title":"Genome-wide association study reveals genetic risk underlying Parkinson\u2019s disease","volume":"41","author":"Sim\u00f3n-S\u00e1nchez","year":"2009","journal-title":"Nature Genetics"},{"key":"bib47","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2112712119","type":"journal-article","article-title":"Nanobodies as allosteric modulators of Parkinson\u2019s disease-associated LRRK2","volume":"119","author":"Singh","year":"2022","journal-title":"PNAS"},{"key":"bib48","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.12813","type":"journal-article","article-title":"Phosphoproteomics reveals that Parkinson\u2019s disease kinase LRRK2 regulates a subset of Rab GTPases","volume":"5","author":"Steger","year":"2016","journal-title":"eLife"},{"key":"bib49","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1042\/BCJ20230126","type":"journal-article","article-title":"Capturing the domain crosstalk in full length LRRK2 and LRRK2RCKW","volume":"480","author":"St\u00f6rmer","year":"2023","journal-title":"The Biochemical Journal"},{"key":"bib50","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2020.538219","type":"journal-article","article-title":"Kinase domain is a dynamic hub for driving LRRK2 Allostery","volume":"13","author":"Taylor","year":"2020","journal-title":"Frontiers in Molecular Neuroscience"},{"key":"bib51","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0023207","type":"journal-article","article-title":"LRRK2 kinase activity is dependent on LRRK2 GTP binding capacity but independent of LRRK2 GTP binding","volume":"6","author":"Taymans","year":"2011","journal-title":"PLOS ONE"},{"key":"bib52","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-023-00544-7","type":"journal-article","article-title":"Perspective on the current state of the LRRK2 field","volume":"9","author":"Taymans","year":"2023","journal-title":"NPJ Parkinson\u2019s Disease"},{"key":"bib53","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/BF00928361","type":"journal-article","article-title":"Physiological concentrations of purines and pyrimidines","volume":"140","author":"Traut","year":"1994","journal-title":"Molecular and Cellular Biochemistry"},{"key":"bib54","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1126\/science.1062023","type":"journal-article","article-title":"The guanine nucleotide-binding switch in three dimensions","volume":"294","author":"Vetter","year":"2001","journal-title":"Science"},{"key":"bib55","doi-asserted-by":"publisher","first-page":"1447","DOI":"10.1515\/hsz-2018-0227","type":"journal-article","article-title":"Biochemical and kinetic properties of the complex Roco G-protein cycle","volume":"399","author":"Wauters","year":"2018","journal-title":"Biological Chemistry"},{"key":"bib56","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.jmb.2011.07.033","type":"journal-article","article-title":"Autophosphorylation in the leucine-rich repeat kinase 2 (LRRK2) GTPase domain modifies kinase and GTP-binding activities","volume":"412","author":"Webber","year":"2011","journal-title":"Journal of Molecular Biology"},{"key":"bib57","doi-asserted-by":"publisher","DOI":"10.3390\/biom11081101","type":"journal-article","article-title":"LRRK2 targeting strategies as potential treatment of Parkinson\u2019s Disease","volume":"11","author":"Wojewska","year":"2021","journal-title":"Biomolecules"},{"key":"bib58","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1126\/science.adi9926","type":"journal-article","article-title":"Human RAB24, interestingly and predominantly distributed in the nuclei of COS-7 cells, is colocalized with cyclophilin A and GABARAP","volume":"17","author":"Wu","year":"2006","journal-title":"International Journal of Molecular Medicine"},{"key":"bib59","doi-asserted-by":"publisher","DOI":"10.1101\/676627","type":"preprint","article-title":"A Revised 1.6 \u00c5 structure of the GTPase Domain of the Parkinson\u2019s Disease-Associated protein LRRK2 provides insights into mechanisms","volume-title":"bioRxiv","author":"Wu","year":"2019"},{"key":"bib60","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1016\/j.neuron.2004.11.005","type":"journal-article","article-title":"Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology","volume":"44","author":"Zimprich","year":"2004","journal-title":"Neuron"},{"key":"dataset1","doi-asserted-by":"publisher","DOI":"10.5281\/zenodo.11242229","type":"dataset","article-title":"Supplemental data for \"Intramolecular feedback regulation of the LRRK2 Roc G domain by a LRRK2 kinase dependent mechanism\"","volume-title":"Zenodo","author":"Gilsbach","year":"2024","unstructured":"Gilsbach BK, FY Ho, Zhang X, Kortholt A, Gloeckner CJ. 2024. Supplemental data for \"Intramolecular feedback regulation of the LRRK2 Roc G domain by a LRRK2 kinase dependent mechanism\". Zenodo."}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/91083\/elife-91083-v1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/91083\/elife-91083-v1.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/91083","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T09:56:40Z","timestamp":1787565400000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/91083"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,19]]},"references-count":61,"alternative-id":["10.7554\/eLife.91083"],"URL":"https:\/\/doi.org\/10.7554\/elife.91083","archive":["CLOCKSS"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.07.31.549909","asserted-by":"subject"}],"is-same-as":[{"id-type":"doi","id":"10.7554\/eLife.91083.4","asserted-by":"subject"}],"is-version-of":[{"id-type":"doi","id":"10.7554\/eLife.91083.1","asserted-by":"subject"},{"id-type":"doi","id":"10.7554\/eLife.91083.2","asserted-by":"subject"},{"id-type":"doi","id":"10.7554\/eLife.91083.3","asserted-by":"subject"}],"is-supplemented-by":[{"id-type":"doi","id":"10.5281\/zenodo.11242229","asserted-by":"subject"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,19]]},"assertion":[{"value":"single anonymised","name":"peer_review_transparency","label":"Peer review transparency","group":{"name":"peer_review_taxonomy"}},{"value":"other reviewer(s), editor","name":"peer_review_interaction","label":"Peer review interaction","group":{"name":"peer_review_taxonomy"}},{"value":"review summaries, review reports, author\/editor communication, reviewer identities reviewer opt in, editor identities","name":"peer_review_published","label":"Peer review published","group":{"name":"peer_review_taxonomy"}},{"value":"open (sign in with ORCID iD required)","name":"post_publication_commenting","label":"Post publication commenting","group":{"name":"post_publication_commenting"}}],"article-number":"RP91083"}}