Site-Specific Detection and Characterization of Ubiquitin Carbamylation.
Site-Specific Detection and Characterization of Ubiquitin Carbamylation.
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DOI：
10.1021/acs.biochem.2c00085
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发表时间：
2022-04-19
期刊：
影响因子：
2.9
通讯作者：
Fushman, David
中科院分区：
文献类型：
--
作者：
Pawloski, Westley;Komiyama, Teppei;Kougentakis, Christos;Majumdar, Ananya;Fushman, David
The physiological consequences of varying in vivo CO2 levels point to a general mechanism for CO2 to influence cellular homeostasis beyond regulating pH. Aside from a few instances where CO2 has been observed to cause post-translational protein modification, by forming long-lived carbamates, little is known about how transitory and ubiquitous carbamylation events could induce a physiological response. Ubiquitin is a versatile protein involved in a multitude of cellular signaling pathways as polymeric chains of various lengths formed through one of the seven lysines or N-terminal amine. Unique polyubiquitin compositions present recognition signals for specific ubiquitin-receptors which enables this one protein to be involved in many different cellular processes. Advances in proteomic methods have allowed capture and identification of protein carbamates in vivo, and Ub was found carbamylated at lysines K48 and K33. This was shown to negatively regulate ubiquitin-mediated signaling by inhibiting polyubiquitin chain formation. Here we expand upon these observations by characterizing the carbamylation susceptibility for all Ub amines simultaneously. Using NMR methods which directly probe 15N resonances we determined carbamylation rates under various environmental conditions and related them to the intrinsic pKas. Our results show that the relatively low pKas for half of the Ub amines are correlated with enhanced susceptibility to carbamylation under physiological conditions. Two of these carbamylated amines, not observed by chemical capture, appear to be physiologically relevant post-translational modifications. These findings point to a mechanism for varying levels of CO2 due to intracellular localization, cellular stresses, and metabolism to affect certain polyubiquitin-mediated signaling pathways.
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