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Cryo-EM analysis of homodimeric full-length LRRK2 and LRRK1 protein complexes

Sejwal, K; Chami, M; Remigy, H; Vancraenenbroeck, R; Sibran, W; Suetterlin, R; Baumgartner, P; ... Taymans, J-M; + view all (2017) Cryo-EM analysis of homodimeric full-length LRRK2 and LRRK1 protein complexes. Scientific Reports , 7 , Article 8667. 10.1038/s41598-017-09126-z. Green open access

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Abstract

Leucine-rich repeat kinase 2 (LRRK2) is a large multidomain protein implicated in the pathogenesis of both familial and sporadic Parkinson’s disease (PD), and currently one of the most promising therapeutic targets for drug design in Parkinson’s disease. In contrast, LRRK1, the closest homologue to LRRK2, does not play any role in PD. Here, we use cryo-electron microscopy (cryo-EM) and single particle analysis to gain structural insight into the full-length dimeric structures of LRRK2 and LRRK1. Differential scanning fluorimetry-based screening of purification buffers showed that elution of the purified LRRK2 protein in a high pH buffer is beneficial in obtaining high quality cryo-EM images. Next, analysis of the 3D maps generated from the cryo-EM data show 16 and 25 Å resolution structures of full length LRRK2 and LRRK1, respectively, revealing the overall shape of the dimers with two-fold symmetric orientations of the protomers that is closely similar between the two proteins. These results suggest that dimerization mechanisms of both LRRKs are closely related and hence that specificities in functions of each LRRK are likely derived from LRRK2 and LRRK1’s other biochemical functions. To our knowledge, this study is the first to provide 3D structural insights in LRRK2 and LRRK1 dimers in parallel.

Type: Article
Title: Cryo-EM analysis of homodimeric full-length LRRK2 and LRRK1 protein complexes
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41598-017-09126-z
Publisher version: https://doi.org/10.1038/s41598-017-09126-z
Language: English
Additional information: Copyright © The Author(s) 2017. This article is Open Access and licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Te images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses /by/4.0/.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: http://discovery.ucl.ac.uk/id/eprint/10065559
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