Ubiquitin carboxy-terminal hydrolase L1

Ubiquitin carboxy-terminal hydrolase L1 (, ubiquitin C-terminal hydrolase, UCH-L1) is a is_associated_with::deubiquitinating enzyme.

Function
UCH-L1 is a member of a gene family whose products hydrolyze small C-terminal adducts of ubiquitin to generate the ubiquitin monomer. Expression of UCH-L1 is highly specific to neurons and to cells of the diffuse neuroendocrine system and their tumors. It is abundantly present in all neurons (accounts for 1-2% of total brain protein), expressed specifically in neurons and testis/ovary.

Relevance to neurodegenerative disorders
A is_associated_with::point mutation (I93M) in the is_associated_with::gene encoding this protein is implicated as the cause of is_associated_with::Parkinson's disease in one German family, although this finding is controversial, as no other Parkinson's disease patients with this mutation have been found

Furthermore, a polymorphism (S18Y) in this gene has been found to be associated with a reduced risk for Parkinson's disease. This polymorphism has specifically been shown to have antioxidant activity.

Another potentially protective function of UCH-L1 is its reported ability to stabilize monois_associated_with::ubiquitin, an important component of the is_associated_with::ubiquitin proteasome system. It is thought that by stabilizing the monomers of ubiquitin and thereby preventing their degradation, UCH-L1 increases the available pool of ubiquitin to be tagged onto proteins destined to be degraded by the proteasome.

The gene is also associated with is_associated_with::Alzheimer's disease, and required for normal synaptic and is_associated_with::cognitive function. Loss of Uchl1 increases the susceptibility of pancreatic beta-cells to programmed cell death, indicating that this protein plays a protective role in neuroendocrine cells and illustrating a link between diabetes and neurodegenerative diseases.

Ectopic expression
Although UCH-L1 protein expression is specific to is_associated_with::neurons and testis/ovary tissue, it has been found to be expressed in certain lung-tumor cell lines. This abnormal expression of UCH-L1 is implicated in cancer and has led to the designation of UCH-L1 as an is_associated_with::oncogene.

Protein structure
Human UCH-L1 and the closely related protein is_associated_with::UCHL3 have one of the most complicated knot structure yet discovered for a protein, with five knot crossings. It is speculated that a knot structure may increase a protein's resistance to degradation in the is_associated_with::proteasome.

The conformation of the UCH-L1 protein may also be an important indication of neuroprotection or pathology. For example, the UCH-L1 dimer has been shown to exhibit the potentially pathogenic ligase activity and may lead to the aforementioned increase in aggregation of α-synuclein. The S18Y polymorphism of UCH-L1 has been shown to be less-prone to dimerization.

Interactions
Ubiquitin carboxy-terminal hydrolase L1 has been shown to interact with is_associated_with::COP9 constitutive photomorphogenic homolog subunit 5.

UCH-L1 has also been shown to interact with is_associated_with::α-synuclein, another protein implicated in the pathology of is_associated_with::Parkinson disease. This activity is reported to be the result of its ubiquityl ligase activity which may be associated with the I93M pathogenic mutation in the gene.

Most recently, UCH-L1 has been demonstrated to interact with the E3 ligase, is_associated_with::parkin. Parkin has been demonstrated to bind and ubiquitinylate UCH-L1 to promote is_associated_with::lysosomal degradation of UCH-L1.