Disease relevance of UCHL3

• Because the amino acid sequence of UCH-L1 is similar to that of other ubiquitin C-terminal hydrolases, including the ubiquitously expressed UCH-L3, which appear to be unconnected to neurodegenerative disease, the structure of UCH-L1 and the effects of disease associated mutations on the structure and function are of considerable importance [1].
• UCH-L3 mRNA level was significantly upregulated in breast cancer tissue compared to adjacent normal breast tissue (P < 0.005), and UHC-L1 mRNA level also showed a non-significant increase in tumor tissue compared to adjacent normal breast tissue [2].
• One fraction that exhibited reactivity with 9/15 colon cancer sera was subjected to mass spectrometry leading to the identification of ubiquitin C-terminal hydrolase isozyme 3 (UCH-L3) as a constituent [3].

High impact information on UCHL3

• A complementary DNA (cDNA) for ubiquitin carboxyl-terminal hydrolase isozyme L3 was cloned from human B cells [4].
• Papain and UCH-L3 differ, however, in strand and helix connectivity, which in the UCH-L3 structure includes a disordered 20 residue loop (residues 147-166) that is positioned over the active site and may function in the definition of substrate specificity [5].
• Crystal structure of a deubiquitinating enzyme (human UCH-L3) at 1.8 A resolution [5].
• The beta-sheet and one of the helices resemble the well-known papain-like cysteine proteases, with the greatest similarity to cathepsin B. This similarity includes the UCH-L3 active site catalytic triad of Cys95, His169 and Asp184, and the oxyanion hole residue Gln89 [5].
• The UCH-L3 active site cleft appears to be masked in the unliganded structure by two different segments of the enzyme (residues 9-12 and 90-94), thus implying a conformational change upon substrate binding and suggesting a mechanism to limit non-specific hydrolysis [5].

Biological context of UCHL3

• Molecular cloning of chick UCH-6 which shares high similarity with human UCH-L3: its unusual substrate specificity and tissue distribution [6].
• All analogues showed weak inhibition toward the catalytic domain of UCH-L3 and a UBP pseudogene [7].

Anatomical context of UCHL3

• Yet UCHL-3 expression was reduced in the cerebral cortex of PD and DLB patients [8].

Associations of UCHL3 with chemical compounds

• By utilizing high-throughput screening (HTS) to find inhibitors and traditional medicinal chemistry to optimize their affinity and specificity, we have identified a class of isatin O-acyl oximes that selectively inhibit UCH-L1 as compared to its systemic isoform, UCH-L3 [9].
• UCH-6 belonged to members of the UCH family containing highly conserved Cys, His, and Asp domains and showed 86% amino acid identity to human UCH-L3 [6].

Enzymatic interactions of UCHL3

• However, UCH-L3 had no detectable activity toward ubiquitinated I kappa B alpha, thus suggesting a degree of enzymatic specificity in the deubiquitination of I kappa B alpha [10].

Other interactions of UCHL3

• The activity of the C-terminal hydrolases UCH-L3 and UCH37 was upregulated in the majority of tumor tissues compared to the adjacent normal tissues [11].
• To develop an enzymatic assay for the search of UCH-L3 and USP2 inhibitors, C-terminally labeled ubiquitin substrates were enzymatically synthesized [12].
• To determine whether specificity may be conferred by recognition of a primary cognate sequence, the substrate preferences of two DUBs, UCH-L3 and isopeptidase T (IsoT), were profiled using a positional scanning branched peptide library [13].

Analytical, diagnostic and therapeutic context of UCHL3

• The site on UCH-L3 was modeled based on X-ray crystallography, multiple sequence alignments, and computer-aided docking [14].
• To validate the occurrence of autoantibodies to UCH-L3, independent analysis was done by means of Western blots [3].
• UCH-L1 and UCH-L3 mRNA levels in invasive breast cancer (n = 100) were determined by a real-time polymerase chain reaction (PCR) assay and their relationship with various clinicopathological characteristics of breast tumors as well as patient prognosis were studied [2].
• In addition, we have used a ubiquitin-based probe in the structural analysis of the ligand-bound form of the enzyme UCH-L3 by x-ray crystallography [15].

References