Structural model of the dimeric Parkinson's protein LRRK2 reveals a compact architecture involving distant interdomain contacts.

TitleStructural model of the dimeric Parkinson's protein LRRK2 reveals a compact architecture involving distant interdomain contacts.
Publication TypeJournal Article
Year of Publication2016
AuthorsGuaitoli, G., F. Raimondi, B. K. Gilsbach, Y. Gómez-Llorente, E. Deyaert, F. Renzi, X. Li, A. Schaffner, P. Kumar Anku Jagtap, K. Boldt, F. von Zweydorf, K. Gotthardt, D. D. Lorimer, Z. Yue, A. Burgin, N. Janjic, M. Sattler, W. Versées, M. Ueffing, I. Ubarretxena-Belandia, A. Kortholt, and C. Johannes Gloeckner
JournalProc Natl Acad Sci U S A
Date Published2016 07 26
KeywordsAmino Acid Sequence, Catalytic Domain, Crystallography, X-Ray, HEK293 Cells, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Models, Molecular, Mutation, Parkinson Disease, Protein Domains, Protein Multimerization, Sequence Homology, Amino Acid

Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein containing two catalytic domains: a Ras of complex proteins (Roc) G-domain and a kinase domain. Mutations associated with familial and sporadic Parkinson's disease (PD) have been identified in both catalytic domains, as well as in several of its multiple putative regulatory domains. Several of these mutations have been linked to increased kinase activity. Despite the role of LRRK2 in the pathogenesis of PD, little is known about its overall architecture and how PD-linked mutations alter its function and enzymatic activities. Here, we have modeled the 3D structure of dimeric, full-length LRRK2 by combining domain-based homology models with multiple experimental constraints provided by chemical cross-linking combined with mass spectrometry, negative-stain EM, and small-angle X-ray scattering. Our model reveals dimeric LRRK2 has a compact overall architecture with a tight, multidomain organization. Close contacts between the N-terminal ankyrin and C-terminal WD40 domains, and their proximity-together with the LRR domain-to the kinase domain suggest an intramolecular mechanism for LRRK2 kinase activity regulation. Overall, our studies provide, to our knowledge, the first structural framework for understanding the role of the different domains of full-length LRRK2 in the pathogenesis of PD.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID27357661
PubMed Central IDPMC4968714
Grant ListS10 RR026473 / RR / NCRR NIH HHS / United States
T32 GM062754 / GM / NIGMS NIH HHS / United States
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