Ubiquitin S65 phosphorylation engenders a pH-sensitive conformational switch

doi:10.1073/pnas.1705718114

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	Ubiquitin S65 phosphorylation engenders a pH-sensitive conformational switch
	Liu, Zhu 3; Zhang, Wei-Ping 3,6; Tang, Chun 1,4,5,7; Dong, Xu 4,7; Gong, Zhou 4,7; Lu, Yun-Bi 3; Liu, Kan 4,7; Qin, Ling-Yun 4,7; Ran, Meng-Lin 4,7; Zhang, Chang-Li 2
刊名	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
	2017-06-27
卷号	114 期号:26 页码:6770-6775
关键词	Ubiquitin Phosphorylation Protein Dynamics Ph Sensitivity Conformational Switch
DOI	10.1073/pnas.1705718114
文献子类	Article
英文摘要	Ubiquitin (Ub) is an important signaling protein. Recent studies have shown that Ub can be enzymatically phosphorylated at S65, and that the resulting pUb exhibits two conformational states-a relaxed state and a retracted state. However, crystallization efforts have yielded only the structure for the relaxed state, which was found similar to that of unmodified Ub. Here we present the solution structures of pUb in both states obtained through refinement against state-specific NMR restraints. We show that the retracted state differs from the relaxed state by the retraction of the last beta-strand and by the extension of the second alpha-helix. Further, we show that at 7.2, the pK(a) value for the phosphoryl group in the relaxed state is higher by 1.4 units than that in the retracted state. Consequently, pUb exists in equilibrium between protonated and deprotonated forms and between retracted and relaxed states, with protonated/relaxed species enriched at slightly acidic pH and deprotonated/retracted species enriched at slightly basic pH. The heterogeneity of pUb explains the inability of phosphomimetic mutants to fully mimic pUb. The pH-sensitive conformational switch is likely preserved for polyubiquitin, as single-molecule FRET data indicate that pH change leads to quaternary rearrangement of a phosphorylated K63-linked diubiquitin. Because cellular pH varies among compartments and changes upon pathophysiological insults, our finding suggests that pH and Ub phosphorylation confer additional target specificities and enable an additional layer of modulation for Ub signals.
WOS关键词	PROTEIN STRUCTURES ; CHEMICAL-SHIFTS ; AMINO-ACIDS ; INTRACELLULAR PH ; ACTIVATE PARKIN ; LIGASE ACTIVITY ; NMR ; PINK1 ; MODEL ; AUTOPHAGY
WOS研究方向	Science & Technology - Other Topics
语种	英语
WOS记录号	WOS:000404108400056
资助机构	Chinese Ministry of Science and Technology(2013CB910200 ; Chinese Ministry of Science and Technology(2013CB910200 ; National Natural Science Foundation of China(31225007 ; National Natural Science Foundation of China(31225007 ; K.C. Wong Education Foundation ; K.C. Wong Education Foundation ; China Postdoctoral Science Foundation(2015M571860 ; China Postdoctoral Science Foundation(2015M571860 ; Howard Hughes Medical Institute ; Howard Hughes Medical Institute ; 2016YFA0501200) ; 2016YFA0501200) ; 81573400 ; 81573400 ; 2016T90537) ; 2016T90537) ; 31500595 ; 31500595 ; 31400735 ; 31400735 ; 31400644) ; 31400644) ; Chinese Ministry of Science and Technology(2013CB910200 ; Chinese Ministry of Science and Technology(2013CB910200 ; National Natural Science Foundation of China(31225007 ; National Natural Science Foundation of China(31225007 ; K.C. Wong Education Foundation ; K.C. Wong Education Foundation ; China Postdoctoral Science Foundation(2015M571860 ; China Postdoctoral Science Foundation(2015M571860 ; Howard Hughes Medical Institute ; Howard Hughes Medical Institute ; 2016YFA0501200) ; 2016YFA0501200) ; 81573400 ; 81573400 ; 2016T90537) ; 2016T90537) ; 31500595 ; 31500595 ; 31400735 ; 31400735 ; 31400644) ; 31400644)
内容类型	期刊论文
源URL	[http://ir.wipm.ac.cn/handle/112942/11472]
专题	武汉物理与数学研究所_磁共振应用研究部
作者单位	1.Chinese Acad Sci, Collaborat Innovat Ctr Chem Life Sci, Wuhan Inst Phys & Math, Wuhan 430071, Hubei Province, Peoples R China 2.Guilin Med Univ, Guilin 541004, Guangxi Provinc, Peoples R China 3.Zhejiang Univ, Sch Med, Key Lab Med Neurobiol, Dept Pharmacol,Inst Neurosci,Minist Hlth China, Hangzhou 310058, Zhejiang, Peoples R China 4.Chinese Acad Sci, Natl Ctr Magnet Resonance Wuhan, Wuhan Inst Phys & Math, Wuhan 430071, Hubei Province, Peoples R China 5.Wuhan Natl Lab Optoelect, Wuhan 430074, Hubei Province, Peoples R China 6.Zhejiang Univ, Sch Med, Zhejiang Prov Key Lab Mental Disorders Management, Hangzhou 310058, Zhejiang, Peoples R China 7.Chinese Acad Sci, Key Lab Magnet Resonance Biol Syst, State Key Lab Magnet Resonance & Atom Mol Phys, Wuhan Inst Phys & Math, Wuhan 430071, Hubei Province, Peoples R China
推荐引用方式 GB/T 7714	Liu, Zhu,Zhang, Wei-Ping,Tang, Chun,et al. Ubiquitin S65 phosphorylation engenders a pH-sensitive conformational switch[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2017,114(26):6770-6775.
APA	Liu, Zhu.,Zhang, Wei-Ping.,Tang, Chun.,Dong, Xu.,Gong, Zhou.,...&Zhang, Chang-Li.(2017).Ubiquitin S65 phosphorylation engenders a pH-sensitive conformational switch.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,114(26),6770-6775.
MLA	Liu, Zhu,et al."Ubiquitin S65 phosphorylation engenders a pH-sensitive conformational switch".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 114.26(2017):6770-6775.