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

Sejwal, Kushal and Chami, Mohamed and Rémigy, Hervé and Vancraenenbroeck, Renée and Sibran, William and Sütterlin, Rosmarie and Baumgartner, Paul and McLeod, Robert and Chartier-Harlin, Marie-Christine and Baekelandt, Veerle and Stahlberg, Henning and Taymans, Jean-Marc. (2017) Cryo-EM analysis of homodimeric full-length LRRK2 and LRRK1 protein complexes. Scientific Reports, 7 (1). p. 8667.

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Official URL: http://edoc.unibas.ch/56286/

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Stahlberg)
UniBasel Contributors:Stahlberg, Henning
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Nature Publishing Group
e-ISSN:2045-2322
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:12 Oct 2017 10:10
Deposited On:12 Oct 2017 10:10

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