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Translation of the genetic code to proteins was a main focus of biological research before the 1980s. How proteins are removed had remained a neglected area of research. With the discovery of the lysosome, it was suggested that cellular proteins are degraded within this organelle. Yet, a growing body of experimental evidence had strongly suggested that intracellular proteolysis is largely nonlysosomal; however, the mechanism(s) involved had remained obscure. The discovery of modification of protein substrates by ubiquitin and their subsequent degradation by the downstream 26S proteasome has resolved the enigma. Later developments have broadened the scope of the ubiquitin system beyond proteolysis, and we now know that modification by ubiquitin and ubiquitin-like proteins serve many nonproteolytic functions as well.
In the ubiquitin system, the various target substrates are modified by ubiquitin or a ubiquitin-like protein. This modification remodels their surface, affecting, among other properties, their stability, interactions with other proteins, activity, and subcellular localization. At least 10 different modifiers have been described in mammalian cells and conjugation of each of them to its target may result in a different biological effect. In many cases proteins are modified by multiple moieties of ubiquitin that generate a branched polyubiquitin chain. For most proteins, this modification leads to their degradation by the 26S proteasome. Yet, dependent on the character of the internal linkage between the ubiquitin moieties, it can also lead to other effects such as activation of transcriptional regulators. Modification by a single moiety of ubiquitin can target proteins for degradation in the lysosome/vacuole. Conjugation of ubiquitin or ubiquitin-like proteins can serve a variety of nonproteolytic functions, such as modulation of membrane dynamics, or routing of the tagged proteins to their subcellular destination. Ubiquitination is a highly complex, temporally controlled, and tightly regulated process that targets, in a specific manner, numerous cellular …
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