negative regulation of protein K63-linked ubiquitination
Definition
Target type: biologicalprocess
Any process that stops, prevents or reduces the frequency, rate or extent of protein K63-linked ubiquitination. [GOC:TermGenie]
Negative regulation of protein K63-linked ubiquitination is a crucial process that controls the stability, localization, and activity of various proteins by modulating their K63-linked polyubiquitination status. K63-linked ubiquitination, a non-proteolytic form of ubiquitination, is a dynamic process involving the attachment of ubiquitin chains linked through lysine 63 of ubiquitin. These chains often act as signaling platforms, recruiting downstream proteins and modulating protein interactions.
The negative regulation of this process is essential for maintaining cellular homeostasis and preventing aberrant signaling. It involves a complex interplay of enzymes, including deubiquitinases (DUBs) and ubiquitin ligases (E3 ligases), which act in concert to remove or prevent the formation of K63-linked ubiquitin chains.
**Deubiquitinases (DUBs)** play a critical role in removing K63-linked ubiquitin chains from target proteins. DUBs are a diverse group of enzymes with distinct substrate specificities and catalytic mechanisms. They hydrolyze the isopeptide bond between ubiquitin and its target protein, leading to the removal of ubiquitin chains and the restoration of the protein's original state.
**Ubiquitin ligases (E3 ligases)** can also contribute to the negative regulation of K63-linked ubiquitination by promoting the formation of ubiquitin chains that are incompatible with K63-linked ubiquitination or by targeting K63-linked ubiquitin chains for degradation. This process involves the recruitment of specific E3 ligases that are capable of recognizing and binding to K63-linked ubiquitin chains. These E3 ligases can then promote the attachment of other types of ubiquitin chains, such as K48-linked chains, which typically target proteins for proteasomal degradation.
**Factors influencing negative regulation of protein K63-linked ubiquitination:**
- **Cellular context:** The negative regulation of K63-linked ubiquitination can vary depending on the cellular context, such as the type of cell, its developmental stage, and the presence of external stimuli.
- **Specific protein targets:** Different proteins have distinct requirements for K63-linked ubiquitination, and the mechanisms regulating their ubiquitination status can vary accordingly.
- **Signaling pathways:** K63-linked ubiquitination is involved in various signaling pathways, and its regulation is tightly linked to the activation and inactivation of these pathways.
In summary, negative regulation of protein K63-linked ubiquitination is a complex process involving a delicate balance of DUBs and E3 ligases, ensuring the proper control of protein stability, localization, and activity. This intricate regulation plays a crucial role in maintaining cellular homeostasis and preventing aberrant signaling, ultimately contributing to overall cell function and survival.'
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Proteins (2)
| Protein | Definition | Taxonomy |
|---|---|---|
| Phospholipase A-2-activating protein | A phospholipase A-2-activating protein that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q9Y263] | Homo sapiens (human) |
| Protein mono-ADP-ribosyltransferase PARP10 | A protein mono-ADP-ribosyltransferase PARP10 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q53GL7] | Homo sapiens (human) |
Compounds (20)
| Compound | Definition | Classes | Roles |
|---|---|---|---|
| theophylline | dimethylxanthine | adenosine receptor antagonist; anti-asthmatic drug; anti-inflammatory agent; bronchodilator agent; drug metabolite; EC 3.1.4.* (phosphoric diester hydrolase) inhibitor; fungal metabolite; human blood serum metabolite; immunomodulator; muscle relaxant; vasodilator agent | |
| pj-34 | PJ34 : A member of the class of phenanthridines that is 5,6-dihydrophenanthridine substituted at positions 2 and 6 by (N,N-dimethylglycyl)amino and oxo groups, respectively. It is a potent inhibitor of poly(ADP-ribose) polymerases PARP1 and PARP2 (IC50 of 110 nM and 86 nM, respectively) and exhibits anti-cancer, cardioprotective and neuroprotective properties. | phenanthridines; secondary carboxamide; tertiary amino compound | angiogenesis inhibitor; anti-inflammatory agent; antiatherosclerotic agent; antineoplastic agent; apoptosis inducer; cardioprotective agent; EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor; neuroprotective agent |
| leucine | leucine : A branched-chain amino acid that consists of glycine in which one of the hydrogens attached to the alpha-carbon is substituted by an isobutyl group. Leucine: An essential branched-chain amino acid important for hemoglobin formation. | amino acid zwitterion; L-alpha-amino acid; leucine; proteinogenic amino acid; pyruvate family amino acid | algal metabolite; Escherichia coli metabolite; human metabolite; mouse metabolite; plant metabolite; Saccharomyces cerevisiae metabolite |
| phenylalanine | L-phenylalanine : The L-enantiomer of phenylalanine. phenylalanine : An aromatic amino acid that is alanine in which one of the methyl hydrogens is substituted by a phenyl group. Phenylalanine: An essential aromatic amino acid that is a precursor of MELANIN; DOPAMINE; noradrenalin (NOREPINEPHRINE), and THYROXINE. | amino acid zwitterion; erythrose 4-phosphate/phosphoenolpyruvate family amino acid; L-alpha-amino acid; phenylalanine; proteinogenic amino acid | algal metabolite; EC 3.1.3.1 (alkaline phosphatase) inhibitor; Escherichia coli metabolite; human xenobiotic metabolite; micronutrient; mouse metabolite; nutraceutical; plant metabolite; Saccharomyces cerevisiae metabolite |
| tryptophan | tryptophan : An alpha-amino acid that is alanine bearing an indol-3-yl substituent at position 3. Tryptophan: An essential amino acid that is necessary for normal growth in infants and for NITROGEN balance in adults. It is a precursor of INDOLE ALKALOIDS in plants. It is a precursor of SEROTONIN (hence its use as an antidepressant and sleep aid). It can be a precursor to NIACIN, albeit inefficiently, in mammals. | erythrose 4-phosphate/phosphoenolpyruvate family amino acid; L-alpha-amino acid; L-alpha-amino acid zwitterion; proteinogenic amino acid; tryptophan; tryptophan zwitterion | antidepressant; Escherichia coli metabolite; human metabolite; micronutrient; mouse metabolite; nutraceutical; plant metabolite; Saccharomyces cerevisiae metabolite |
| homoarginine | L-homoarginine : An L-lysine derivative that is the L-enantiomer of homoarginine. | homoarginine; L-lysine derivative; non-proteinogenic L-alpha-amino acid | biomarker; EC 3.1.3.1 (alkaline phosphatase) inhibitor; human metabolite; rat metabolite; xenobiotic metabolite |
| levamisole | levamisole : A 6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b][1,3]thiazole that has S configuration. It is used (generally as the monohydrochloride salt) to treat parasitic worm infections in pigs, sheep and cattle and was formerly used in humans as an adjuvant to chemotherapy for the treatment of various cancers. It is also widely used as an adulterant to coccaine. Levamisole: An antihelminthic drug that has been tried experimentally in rheumatic disorders where it apparently restores the immune response by increasing macrophage chemotaxis and T-lymphocyte function. Paradoxically, this immune enhancement appears to be beneficial in rheumatoid arthritis where dermatitis, leukopenia, and thrombocytopenia, and nausea and vomiting have been reported as side effects. (From Smith and Reynard, Textbook of Pharmacology, 1991, p435-6) | 6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b][1,3]thiazole | antinematodal drug; antirheumatic drug; EC 3.1.3.1 (alkaline phosphatase) inhibitor; immunological adjuvant; immunomodulator |
| 1-(3,4-dihydroxyphenyl)-2-(1-imidazolyl)ethanone | aromatic ketone | ||
| 4-Methoxybenzamide | benzamides | ||
| 3,4-dihydro-5-methyl-1(2h)-isoquinolinone | 3,4-dihydro-5-methyl-1(2H)-isoquinolinone: structure given in first source | isoquinolines | |
| 1-oxo-1,2,3,4-tetrahydroisoquinoline | 1-oxo-1,2,3,4-tetrahydroisoquinoline: structure given in first source | ||
| 1-(3,4-dihydroxyphenyl)-2-[(4,6-dimethyl-2-pyrimidinyl)thio]ethanone | aromatic ketone | ||
| 2,5-dimethoxy-n-(quinolin-3-yl)benzenesulfonamide | 2,5-dimethoxy-N-(quinolin-3-yl)benzenesulfonamide: a tissue-nonspecific alkaline phosphatase inhibitor; structure in first source | quinolines | |
| fr 148083 | 5Z-7-oxozeaenol : A macrolide that is the 7-oxo derivative of zeaenol (the 5Z stereoisomer). Isolated from Fungi, it exhibits cytotoxic, antibacterial and inhibitory activity against NF-kappaB. | aromatic ether; macrolide; phenols; secondary alcohol; secondary alpha-hydroxy ketone | antibacterial agent; antineoplastic agent; metabolite; NF-kappaB inhibitor |
| rucaparib | AG14447: Poly(ADP-ribose) polymerase inhibitor; structure in first source | azepinoindole; caprolactams; organofluorine compound; secondary amino compound | antineoplastic agent; EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor |
| veliparib | benzimidazoles | EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor | |
| olaparib | cyclopropanes; monofluorobenzenes; N-acylpiperazine; phthalazines | antineoplastic agent; apoptosis inducer; EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor | |
| niraparib | niraparib : A 2-[4-(piperidin-3-yl)phenyl]-2H-indazole-7-carboxamide that has S-configuration. It is a potent inhibitor of PARP1 and PARP2 (IC50 of 3.8 and 2.1 nM, respectively) and approved as a first-line maintenance treatment for women with advanced ovarian cancer after responding to platinum-based chemotherapy. niraparib: structure in first source | 2-[4-(piperidin-3-yl)phenyl]-2H-indazole-7-carboxamide | antineoplastic agent; apoptosis inducer; EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor; radiosensitizing agent |
| g007-lk | G007-LK: potent and specific small-molecule tankyrase inhibitor; structure in first source | ||
| bmn 673 | talazoparib: inhibits both PARP1 and PARP2; structure in first source |