Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proteins modified by multiubiquitin chains are the preferred substrates of the proteasome. Ubiquitination involves a ubiquitin-activating enzyme, E1, a ubiquitin-conjugating enzyme, E2, and often a substrate-specific ubiquitin-protein ligase, E3. Here we show that efficient multiubiquitination needed for proteasomal targeting of a model substrate requires an additional conjugation factor, named E4. This protein, previously known as UFD2 in yeast, binds to the ubiquitin moieties of preformed conjugates and catalyzes ubiquitin chain assembly in conjunction with E1, E2, and E3. Intriguingly, E4 defines a novel protein family that includes two human members and the regulatory protein NOSA from Dictyostelium required for fruiting body development. In yeast, E4 activity is linked to cell survival under stress conditions, indicating that eukaryotes utilize E4-dependent proteolysis pathways for multiple cellular functions.
 ...
PMID:A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly. 1008 79

Selective protein degradation by the 26S proteasome requires the covalent attachment of several ubiquitin molecules in the form of a multiubiquitin chain. Ubiquitylation usually involves three classes of enzymes: a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2) and a ubiquitin ligase (E3). However, in some cases, multiubiquitylation requires the additional activity of certain ubiquitin-chain elongation factors. Yeast UFD2 (ubiquitin fusion degradation), for example, binds to oligoubiquitylated substrates (proteins modified by only a few ubiquitin molecules) and catalyses multiubiquitin-chain assembly in collaboration with E1, E2 and E3. Enzymes possessing this specific activity have been proposed to be termed 'E4 enzymes'. Recent studies have provided accumulating evidence that has led some researchers in the field to conclude that E4, indeed, represents a distinct and novel class of enzymes.
 ...
PMID:Multiubiquitylation by E4 enzymes: 'one size' doesn't fit all. 1581 94

Selective protein degradation by the 26 S proteasome usually requires a polyubiquitin chain attached to the protein substrate by three classes of enzymes: a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin ligase (E3). This reaction can produce different polyubiquitin chains that, depending on size and linkage type, can provide distinct intracellular signals. Interestingly, polyubiquitination is sometimes regulated by additional conjugation factors, called E4s (polyubiquitin chain conjugation factors). Yeast UFD2 (ubiquitin fusion degradation protein-2), the first E4 to be described, binds to the ubiquitin moieties of preformed conjugates and catalyses ubiquitin-chain elongation together with E1, E2, and E3. Recent studies have illustrated that the E4 enzyme UFD2 co-operates with an orchestra of ubiquitin-binding factors in an escort pathway to transfer and deliver polyubiquitinated substrates to the 26 S proteasome. Here we propose a model in which E4-dependent polyubiquitination pathways are modulated by different ubiquitin-binding proteins, using ataxin-3 as an example.
 ...
PMID:Orchestra for assembly and fate of polyubiquitin chains. 1625 Aug 94

Chromosomes 11q and 1p are commonly deleted in advanced-stage neuroblastomas and are therefore assumed to contain tumour suppressor genes involved in the development of this cancer. The two UFD2 yeast gene human homologues, UBE4A and UBE4B, involved in the ubiquitin/proteasome pathway, are located in 11q and 1p, respectively. UBE4B has previously been analysed for mutations and one mutation in the splice donor site of exon 9, c.1439 + 1G > C, was found in a neuroblastoma tumour with fatal outcome. We speculated that the homologue UBE4A might be involved in an alternative tumourigenesis pathway. The coding exons of UBE4A were therefore sequenced. One putative missense mutation (1028T > C, leading to I343T, residing in exon 8) was found in neuroblastoma tumour 20R8; this finding was confirmed by sequencing in both directions. The change, isoleucine (non-polar) to threonine (polar), was situated in a highly conserved amino acid region. In addition, two novel variants were also found in intronic sequences of UBE4A. It might be speculated that the proteins generated from UBE4B and UBE4A are involved in protecting the cell from environmental stress and that inactivation of either of them could contribute to malignancy.
 ...
PMID:The two human homologues of yeast UFD2 ubiquitination factor, UBE4A and UBE4B, are located in common neuroblastoma deletion regions and are subject to mutations in tumours. 1638 91