气候变化领域集成服务门户(CCPortal): Structural characterization of the D290V mutation site in hnRNPA2 low-complexity-domain polymers

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DOI	10.1073/pnas.1806174115
	Structural characterization of the D290V mutation site in hnRNPA2 low-complexity-domain polymers
	Murray D.T.; Zhou X.; Kato M.; Xiang S.; Tycko R.; McKnight S.L.
发表日期	2018
ISSN	0027-8424
起始页码	E9782
结束页码	E9791
卷号	115 期号:42
英文摘要	Human genetic studies have given evidence of familial, diseasecausing mutations in the analogous amino acid residue shared by three related RNA binding proteins causative of three neurological diseases. Alteration of aspartic acid residue 290 of hnRNPA2 to valine is believed to predispose patients to multisystem proteinopathy. Mutation of aspartic acid 262 of hnRNPA1 to either valine or asparagine has been linked to either amyotrophic lateral sclerosis or multisystem proteinopathy. Mutation of aspartic acid 378 of hnRNPDL to either asparagine or histidine has been associated with limb girdle muscular dystrophy. All three of these aspartic acid residues map to evolutionarily conserved regions of low-complexity (LC) sequence that may function in states of either intrinsic disorder or labile self-association. Here, we present a combination of solid-state NMR spectroscopy with segmental isotope labeling and electron microscopy on the LC domain of the hnRNPA2 protein. We show that, for both the wild-type protein and the aspartic acid 290-to-valine mutant, labile polymers are formed in which the LC domain associates into an in-register cross-β conformation. Aspartic acid 290 is shown to be charged at physiological pH and immobilized within the polymer core. Polymers of the aspartic acid 290-to-valine mutant are thermodynamically more stable than wild-type polymers. These observations give evidence that removal of destabilizing electrostatic interactions may be responsible for the increased propensity of the mutated LC domains to self-associate in diseasecausing conformations. © 2018 National Academy of Sciences. All rights reserved.
英文关键词	Cross-beta polymer; HnRNPA2; Low-complexity sequence; Neurodegenerative disease; Solid-state NMR
语种	英语
scopus关键词	aspartic acid; heterogeneous nuclear ribonucleoprotein group A B; hnRNP A2; polymer; amino acid sequence; chemistry; genetics; human; mutation; nuclear magnetic resonance; protein conformation; protein domain; site directed mutagenesis; Amino Acid Sequence; Aspartic Acid; Heterogeneous-Nuclear Ribonucleoprotein Group A-B; Humans; Mutagenesis, Site-Directed; Mutation; Nuclear Magnetic Resonance, Biomolecular; Polymers; Protein Conformation; Protein Domains
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/160456
作者单位	Murray, D.T., Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Disease, Bethesda, MD 20892, United States, Postdoctoral Research Associate Training Program, National Institute of General Medical Sciences, Bethesda, MD 20892, United States, Department of Chemistry, University of California, Davis, CA 95616, United States; Zhou, X., Department of Biochemistry, University of Texas Southwestern, Medical Center, Dallas, TX 75390, United States; Kato, M., Department of Biochemistry, University of Texas Southwestern, Medical Center, Dallas, TX 75390, United States; Xiang, S., Department of Biochemistry, University of Texas Southwestern, Medical Center, Dallas, TX 75390, United States, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, United States; Tycko, R., Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Disease, Bethesda, MD 20892, United States; McKnight, S.L., Department of Biochemist...
推荐引用方式 GB/T 7714	Murray D.T.,Zhou X.,Kato M.,et al. Structural characterization of the D290V mutation site in hnRNPA2 low-complexity-domain polymers[J],2018,115(42).
APA	Murray D.T.,Zhou X.,Kato M.,Xiang S.,Tycko R.,&McKnight S.L..(2018).Structural characterization of the D290V mutation site in hnRNPA2 low-complexity-domain polymers.Proceedings of the National Academy of Sciences of the United States of America,115(42).
MLA	Murray D.T.,et al."Structural characterization of the D290V mutation site in hnRNPA2 low-complexity-domain polymers".Proceedings of the National Academy of Sciences of the United States of America 115.42(2018).