Parkinson disease-associated mutation R1441H in LRRK2 prolongs the “active state” of its GTPase domain

Jingling Liao; Chun-Xiang Wu; Christopher BurlakSheng ZhangHeather SahmMu WangZhong-Yin ZhangKurt W. VogelMark FedericiSteve M. RiddleR. Jeremy NicholsDali LiuMark R. CooksonTodd A. StoneQuyen Q. Hoang

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Parkinson disease-associated mutation R1441H in LRRK2 prolongs the “active state” of its GTPase domain

机译：Parkinson disease-associated mutation R1441H in LRRK2 prolongs the “active state” of its GTPase domain

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Mutation in leucine-rich-repeat kinase 2 (LRRK2) is a common cause of Parkinson disease (PD). A disease-causing point mutation R1441H/G/C in the GTPase domain of LRRK2 leads to overactivation of its kinase domain. However, the mechanism by which this mutation alters the normal function of its GTPase domain Ras of complex proteins (Roc) remains unclear. Here, we report the effects of R1441H mutation (Roc_(R1441H)) on the structure and activity of Roc. We showthat Roc forms a stable monomeric conformation in solution that is catalytically active, thus demonstrating that LRRK2 is a bona fide self-contained GTPase. We further show that the R1441H mutation causes a twofold reduction in GTPase activity without affecting the structure, thermal stability, and GDP-binding affinity of Roc. However, the mutation causes a twofold increase in GTP-binding affinity of Roc, thus suggesting that the PD-causing mutation R1441H traps Roc in a more persistently activated state by increasing its affinity for GTP and, at the same time, compromising its GTP hydrolysis.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2014年第11期|4055-4060|共6页
作者
Jingling Liao; Chun-Xiang Wu; Christopher BurlakSheng ZhangHeather SahmMu WangZhong-Yin ZhangKurt W. VogelMark FedericiSteve M. RiddleR. Jeremy NicholsDali LiuMark R. CooksonTodd A. StoneQuyen Q. Hoang;
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作者单位

Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202;

Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202;

Thermo Fisher Scientific, Madison, WI 53719The Parkinson’s Institute and Clinical Center, Sunnyvale, CA 94085Loyola University Chicago, Chicago, IL 60626Laboratory of Neurogenetics, National Institutes of Health, Bethesda, MD 20892Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN 47405;

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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
disease-associated; mutation; active;

Parkinson disease-associated mutation R1441H in LRRK2 prolongs the “active state” of its GTPase domain

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