期刊
SCIENTIFIC REPORTS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/srep43748
关键词
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资金
- Medical Research Council [U117533887, U117565398]
- Francis Crick Institute
- Cancer Research UK [FC001142, FC10029]
- UK Medical Research Council [FC001142, FC10029]
- Wellcome Trust [FC001142, FC10029]
- Medical Research Council [MC_U117533887, MC_U117565398] Funding Source: researchfish
- The Francis Crick Institute [10142, 10029] Funding Source: researchfish
- MRC [MC_U117565398, MC_U117533887] Funding Source: UKRI
Ubiquitination regulates nearly every aspect of cellular life. It is catalysed by a cascade of three enzymes and results in the attachment of the C-terminal carboxylate of ubiquitin to a lysine side chain in the protein substrate. Chain extension occurs via addition of subsequent ubiquitin molecules to either one of the seven lysine residues of ubiquitin, or via its N-terminal a-amino group to build linear ubiquitin chains. The pKa of lysine side chains is around 10.5 and hence E3 ligases require a mechanism to deprotonate the amino group at physiological pH to produce an effective nucleophile. In contrast, the pK(a) of N-terminal alpha-amino groups of proteins can vary significantly, with reported values between 6.8 and 9.1, raising the possibility that linear chain synthesis may not require a general base. In this study we use NMR spectroscopy to determine the pK(a) for the N-terminal alpha-amino group of methionine1 of ubiquitin for the first time. We show that it is 9.14, one of the highest pK(a) values ever reported for this amino group, providing a rational for the observed need for a general base in the E3 ligase HOIP, which synthesizes linear ubiquitin chains.
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