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

Guaitoli Giambattista; Raimondi Francesco; Gilsbach Bernd K.Gomez-Llorente YacobDeyaert EgonRenzi FabianaLi XiantingSchaffner AdamJagtap Pravin Kumar AnkushBoldt Karstenvon Zweydorf FelixGotthardt KatjaLorimer Donald D.Yue ZhenyuBurgin AlexJanjic NebojsaSattler MichaelVersees WimUeffing MariusUbarretxena-Belandia IbanKortholt ArjanGloeckner Christian Johannes

首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America. >Structural model of the dimeric Parkinson's protein LRRK2 reveals a compact architecture involving distant interdomain contacts

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

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

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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.

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《Proceedings of the National Academy of Sciences of the United States of America.》 |2016年第30期|E4357-E4366|共10页
作者
Guaitoli Giambattista; Raimondi Francesco; Gilsbach Bernd K.Gomez-Llorente YacobDeyaert EgonRenzi FabianaLi XiantingSchaffner AdamJagtap Pravin Kumar AnkushBoldt Karstenvon Zweydorf FelixGotthardt KatjaLorimer Donald D.Yue ZhenyuBurgin AlexJanjic NebojsaSattler MichaelVersees WimUeffing MariusUbarretxena-Belandia IbanKortholt ArjanGloeckner Christian Johannes;
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作者单位

Icahn Sch Med Mt Sinai, Dept Struct & Chem Biol, New York, NY 10029 USA;

German Ctr Neurodegenerat Dis, D-72076 Tubingen, Germany;

Vrije Univ Brussel, Struct Biol Brussels, B-1050 Brussels, BelgiumUniv Modena & Reggio Emilia, Dept Life Sci, I-41125 Modena, ItalyIcahn Sch Med Mt Sinai, Friedman Brain Inst, Dept Neurol, New York, NY 10029 USATech Univ Munich, Dept Chem, Ctr Integrated Prot Sci Munich, D-85747 Garching, GermanyUniv Tubingen, Inst Ophthalm Res, Ctr Ophthalmol, D-72076 Tubingen, GermanyMax Planck Inst Mol Physiol, Struct Biol Grp, D-44227 Dortmund, GermanyBeryllium Discovery Corp, Bainbridge Isl, WA 98110 USABroad Inst, Cambridge, MA 02142 USASomaLogic, Boulder, CO 80301 USAUniv Groningen, Dept Cell Biochem, NL-9747 AG Groningen, Netherlands;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
LRRK2; Parkinson's disease; structural modeling; EM; CL-MS;

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

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