Ubiquitin carboxy-terminal hydrolase L1 (, ''ubiquitin C-terminal hydrolase'', ''UCH-L1'') is a

deubiquitinating enzyme Deubiquitinating enzymes (DUBs), also known as deubiquitinating peptidases, deubiquitinating isopeptidases, deubiquitinases, ubiquitin proteases, ubiquitin hydrolases, or ubiquitin isopeptidases, are a large group of proteases that cleave ubiquiti ...

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. The catalytic triad of UCH-L1 contains a cysteine at position 90, an aspartate at position 176, and a histidine at position 161 that are responsible for its hydrolase activity.

Relevance to neurodegenerative disorders

point mutation A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences ...

(I93M) in the

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

encoding this protein is implicated as the cause of

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

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 mono

ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 19 ...

, an important component of the

ubiquitin proteasome system Proteasomes are essential protein complexes responsible for the degradation of proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are found inside all e ...

. 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

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

, and required for normal synaptic and

cognitive Cognition is the "mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...

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. Patients with early-onset neurodegeneration in which the causative mutation was in the UCHL1 gene (specifically, the ubiquitin binding domain, E7A) display blindness, cerebellar ataxia, nystagmus, dorsal column dysfunction, and upper motor neuron dysfunction.

Ectopic expression

Although UCH-L1 protein expression is specific to

neurons A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

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

oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

. Furthermore there is evidence that UCH-L1 might play a role in the pathogenesis of membranous glomerulonephritis as UCH-L1 de novo expression in podocytes was seen in PHN, the rat model of human mGN. This UCH-L1 expression is thought to induce at least in part podocyte hypertrophy.

Protein structure

Human UCH-L1 and the closely related protein

UCHL3 Ubiquitin carboxyl-terminal hydrolase isozyme L3 is an enzyme that in humans is encoded by the ''UCHL3'' gene. Interactions UCHL3 has been shown to interact with NEDD8 and the tauopathy and synucleinopathy associated mutated ubiquitin molecule UB ...

have one of the most complicated

knot A knot is an intentional complication in Rope, cordage which may be practical or decorative, or both. Practical knots are classified by function, including List of hitch knots, hitches, List of bend knots, bends, List of loop knots, loop knots, ...

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

proteasome Proteasomes are essential protein complexes responsible for the degradation of proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are found inside all e ...

. 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 Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization advocating for the legal and human rights of children with intersex traits. The organization was founded in 2006 and fo ...

with

COP9 constitutive photomorphogenic homolog subunit 5 COP9 constitutive photomorphogenic homolog subunit 5 (Arabidopsis), also known as COPS5 or Csn5, is a gene conserved from humans to Saccharomyces cerevisiae. Function The protein encoded by this gene is one of the eight subunits of COP9 sign ...

. UCH-L1 has also been shown to interact with

α-synuclein Alpha-synuclein (aSyn) is a protein that in humans is encoded by the ''SNCA'' gene. It is a neuronal protein involved in the regulation of synaptic vesicle trafficking and the release of neurotransmitters. Alpha-synuclein is abundant in the bra ...

, another protein implicated in the pathology of

Parkinson disease Parkinson may refer to: *Parkinson (surname) * ''Parkinson'' (TV series), British chat show, presented by Sir Michael Parkinson *Parkinson, Queensland, suburb of Brisbane, Australia *The Parkinsons (fl. early 20th century), American father-and-son ...

. 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, parkin. Parkin has been demonstrated to bind and ubiquitinylate UCH-L1 to promote

lysosomal degradation A lysosome () is a membrane-bound organelle that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...

of UCH-L1.

References

External links

* * {{Portal bar, Biology, border=no EC 3.1.2 Molecular neuroscience