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Contact details

Georgios A. Spyroulias, PhD.
Department of Pharmacy
University of Patras
GR-26504 Patras, GREECE
Tel:    +30.2610.969950 (office)
+30.2610.969951 (terra silico)
+30.2610.969952 (terra vitro)
Fax:    +30.2610.969950
Email:  G.A.Spyroulias@upatras.gr

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Now is: 2019-12-07 23:02
E3 Ubiquitin Ligases – RING finger structures and protein socialization in Ubiquitination Pathway
target3In eukaryotic cells, many short-lived proteins are conjugated with Lys 48-linked ubiquitin chains and degraded by the proteasome. Ubiquitination process requires an activating enzyme (E1), a conjugating enzyme (E2) and a ligase (E3) for the effective transfer and attachment of the ubiquitin to the protein-target. Most ubiquitin ligases use either a HECT (homologous to E6-associated protein C terminus) or a RING (really interesting new gene) domain to catalyse polyubiquitination, but the mechanism of E3 catalysis is poorly defined {Nature Insight: The Ubiquitin System, Nature. Vol 458, Iss. 7237, (2009)}.
RING finger domains are polypeptides rich in cysteine residues and bind two Zinc(II) ions per molecule with a distinct way than the common Zinc-fingers. Seven or six cysteins along with one or two histidines, respectively, bind the metal ion in a characteristic “cross-braced” manner. RING fingers often form homo- or hetero-dimers with other RINGs while they firmly interact with E2 enzymes and/or with their protein-targets (substrates) that are programmed to ubiquitinate. The role of the metal ion is believed to be only structural and effective ubiquitination depends on the E2-E3 complex architecture.
Although there is a large number of known E3 enzymes, with RING fingers to be several hundreds, there are only 30-40 known E2 enzymes in humans. Therefore, the selectivity of the RINGs towards their partner E2s remains to be elucidated along with other physicochemical determinants that make an E2-E3 complex a productive one. To this direction the group is involved in the in silico & in vitro SAR studies of Arkadia, MDM2/MDMX and other RING finger E3 ubiquitin ligases.