Enabling Protein Degradation Drug Discovery

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  • Name
    Catalogue Number
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  • Name:
    USP19 -TM(1-1290) [GST-tagged]
    Catalogue Number:
    50 µg
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  • Species
  • Source
  • Quantity
    50 µg
  • Storage
  • Concentration
    0.5 mg/ml
  • Formulation
    50 mM HEPES pH 7.5, 150 mM sodium chloride, 2 mM dithiothreitol, 10% glycerol
  • Molecular Weight
    ~170 kDa
  • Stability
    12 months at -70°C; aliquot as required
  • Protein Sequence
    Accession number: NP_006668. For full protein sequence information download the Certificate of Analysis pdf.
  • QA; Protein Identification
    Confirmed by mass spectrometry.
  • QA; Activity
    Deubiquitylase Enzyme Assay: The activity of GST-USP19 was validated by determining the increase in fluorescence measured as a result of the enzyme catalysed cleavage of the fluorogenic substrate Ubiquitin-Rhodamine110-Glycine generating Ubiquitin and Rhodamine110-Glycine. Incubation of the substrate in the presence or absence of GST-USP19 was compared confirming the deubiquitylating activity of GST-USP19.

Deconjugating enzymes (DCEs) are proteases that process ubiquitin or ubiquitin-like gene products, reverse the modification of proteins by a single ubiquitin or ubiquitin-like protein (UBL) and remodel polyubiquitin (or poly-UBL) chains on target proteins (Reyes-Turcu et al., 2009). The deubiquitylating – or deubiquitinating – enzymes (DUBs) represent the largest family of DCEs and regulate ubiquitin dependent signaling pathways. The activities of the DUBs include the generation of free ubiquitin from precursor molecules, the recycling of ubiquitin following substrate degradation to maintain cellular ubiquitin homeostasis and the removal of ubiquitin or ubiquitin-like proteins (UBL) modifications through chain editing to rescue proteins from proteasomal degradation or to influence cell signalling events (Komander et al., 2009). There are two main classes of DUB; cysteine proteases and metalloproteases. Ubiquitin specific protease 19 (USP19) is a member of the cysteine protease enzyme family and cloning of the human gene was first described by Nagase et al. (1998). USP19 is a ubiquitin-specific protease anchored via its C-terminal to the endoplasmic-reticulum. USP19 rescues the endoplasmic-reticulum-associated degradation (ERAD) substrates:  cystic fibrosis transmembrane conductance regulator (CFTR) and T-cell receptor-α (TCRα) from proteasomal degradation. It also deubiquitylates and prevents proteasomal degradation of RNF123 which in turn stimulates CDKN1B ubiquitin-dependent degradation thereby playing a role in cell proliferation (Hassink et al., 2009). USP19 modulates transcription of major myofibrillar proteins and is involved in decreased protein synthesis in atrophying skeletal muscle. Inhibition of USP19 could be a novel therapeutic mechanism for the prevention and treatment of muscle protein catabolism (Sundaram et al., 2009). During the cell cycle, USP19 regulates p27 levels by deubiquitylating and stabilizing RNF123, an E3 ubiquitin ligase that ubiquitylates p27 and targets it for proteasomal degradation at the G1 phase. Enhanced degradation of p27 in G1 phase is associated with several cancers, and thus USP19 could be a possible target for oncology research (Lu et al., 2009).  Cellular inhibitors of apoptosis (c-IAPs) are stabilised by USP19 in a deubiquitylase-independent mechanism, by inhibiting the self-ubiquitin ligase activity of c-IAPs (Mei et al., 2011).

Hassink GC, Zhao B, Sompallae R, Altun M, Gastaldello S, Zinin NV, Masucci MG, Lindsten K (2009) The ER-resident ubiquitin-specific protease 19 participates in the UPR and rescues ERAD substrates. EMBO Rep 10, 755-761.

Komander D, Clague MJ, Urbe S (2009) Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol 10, 550-563.

Lu Y, Adegoke OA, Nepveu A, Nakayama KI, Bedard N, Cheng D, Peng J, Wing SS (2009) USP19 deubiquitinating enzyme supports cell proliferation by stabilizing KPC1, a ubiquitin ligase for p27Kip1. Mol Cell Biol 29, 547-558.

Mei Y, Hahn AA, Hu S, Yang X (2011) The USP19 deubiquitinase regulates the stability of c-IAP1 and c-IAP2. J Biol Chem 286, 35380-35387.

Nagase T, Ishikawa K, Suyama M, Kikuno R, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (1998) Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res 5, 277-286.

Reyes-Turcu FE, Ventii KH, Wilkinson KD (2009) Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Ann Rev Biochem 78, 363-397.

Sundaram P, Pang Z, Miao M, Yu L, Wing SS (2009) USP19-deubiquitinating enzyme regulates levels of major myofibrillar proteins in L6 muscle cells. Am J Physiol Endocrinol Metab 297, E1283-1290.