Elucidating the mysterious ubiquitin ligase mechanism of Ubiquitin C-terminal Hydrolase-L1 (UCH-L1)
Ubiquitination is a post-translational modification that has emerged as a key regulator of most cellular processes, ranging from subcellular localization to protein function, cell signaling, and protein degradation by the proteasome or the lysosome.
Like other PTMs, ubiquitination is reversible due to the activity of specific protases called deubiquitinating enzymes (DUBs). A unique DUB is ubiquitin C-terminal hydrolase L1 (UCH-L1), which is restricted to the cleavage of small adducts from the C-terminus of ubiquitin.
UCH-L1 is abundantly expressed in neurons, yet its biological function in neuronal cells remains a mystery. Different studies have shown that UCH-L1 plays a role in neurodegeneration. Moreover, we showed that UCH-L1 over-expression delays the accumulation of Alzheimer’s hallmarks, which suggests that UCH-L1 plays a unique role in prolonging neuronal health.
In addition to its extensively studied hydrolase activity as a DUB, we characterize an additional enzymatic activity, in which UCH-L1 acts as a ligase. We succeeded in identifying, for the first time, a new active site that is responsible for this distinct activity. Furthermore, we demonstrated that the two active sites work independently of each other. Additionally, we provide an initial characterization of the enzymatic cascade in which it participates.
We are currently delineating which of the two distinct enzymatic activities is essential for UCH-L1’s role in suppressing Alzheimer’s hallmarks. The investigation into the biochemical mechanisms underlying UCH-L1’s dual enzymatic activities aims to unravel the mystery of its unique function in neurons.