气候变化领域集成服务门户(CCPortal): Mechanistic basis for ubiquitin modulation of a protein energy landscape

CCPortal

DOI	10.1073/pnas.2025126118
	Mechanistic basis for ubiquitin modulation of a protein energy landscape
	Carroll E.C.; Latorraca N.R.; Lindner J.M.; Maguire B.C.; Pelton J.G.; Marqusee S.
发表日期	2021
ISSN	00278424
卷号	118 期号:12
英文摘要	Ubiquitin is a common posttranslational modification canonically associated with targeting proteins to the 26S proteasome for degradation and also plays a role in numerous other nondegradative cellular processes. Ubiquitination at certain sites destabilizes the substrate protein, with consequences for proteasomal processing, while ubiquitination at other sites has little energetic effect. How this site specificity—and, by extension, the myriad effects of ubiquitination on substrate proteins—arises remains unknown. Here, we systematically characterize the atomic-level effects of ubiquitination at various sites on a model protein, barstar, using a combination of NMR, hydrogen–deuterium exchange mass spectrometry, and molecular dynamics simulation. We find that, regardless of the site of modification, ubiquitination does not induce large structural rearrangements in the substrate. Destabilizing modifications, however, increase fluctuations from the native state resulting in exposure of the substrate’s C terminus. Both of the sites occur in regions of barstar with relatively high conformational flexibility. Nevertheless, destabilization appears to occur through different thermodynamic mechanisms, involving a reduction in entropy in one case and a loss in enthalpy in another. By contrast, ubiquitination at a nondestabilizing site protects the substrate C terminus through intermittent formation of a structural motif with the last three residues of ubiquitin. Thus, the biophysical effects of ubiquitination at a given site depend greatly on local context. Taken together, our results reveal how a single posttranslational modification can generate a broad array of distinct effects, providing a framework to guide the design of proteins and therapeutics with desired degradation and quality control properties. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Ubiquitin \| energy landscape \| hydrogen exchange \| molecular dynamics
语种	英语
scopus关键词	ubiquitin; Article; carboxy terminal sequence; controlled study; enthalpy; entropy; hydrogen deuterium exchange-mass spectrometry; information processing; molecular dynamics; nuclear magnetic resonance; priority journal; protein conformation; protein degradation; protein function; protein localization; protein motif; protein purification; protein structure; proteomics; quality control; thermodynamics; ubiquitination
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/180173
作者单位	Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, United States; QB3 Institute for Quantitative Biosciences, University of California, Berkeley, CA 94720, United States; Department of Chemistry, University of California, Berkeley, CA 94720, United States
推荐引用方式 GB/T 7714	Carroll E.C.,Latorraca N.R.,Lindner J.M.,et al. Mechanistic basis for ubiquitin modulation of a protein energy landscape[J],2021,118(12).
APA	Carroll E.C.,Latorraca N.R.,Lindner J.M.,Maguire B.C.,Pelton J.G.,&Marqusee S..(2021).Mechanistic basis for ubiquitin modulation of a protein energy landscape.Proceedings of the National Academy of Sciences of the United States of America,118(12).
MLA	Carroll E.C.,et al."Mechanistic basis for ubiquitin modulation of a protein energy landscape".Proceedings of the National Academy of Sciences of the United States of America 118.12(2021).