4v3k | pdb_00004v3k
RNF38-UbcH5B-UB complex
Structural highlights
Function[UB2D2_HUMAN] Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-48'-linked polyubiquitination. Mediates the selective degradation of short-lived and abnormal proteins. Functions in the E6/E6-AP-induced ubiquitination of p53/TP53. Mediates ubiquitination of PEX5 and autoubiquitination of STUB1 and TRAF6. Involved in the signal-induced conjugation and subsequent degradation of NFKBIA, FBXW2-mediated GCM1 ubiquitination and degradation, MDM2-dependent degradation of p53/TP53 and the activation of MAVS in the mitochondria by DDX58/RIG-I in response to viral infection. Essential for viral activation of IRF3.[1] [2] [3] [4] [5] [6] [7] [8] [UBC_HUMAN] Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.[9] [10] Publication Abstract from PubMedRING ubiquitin ligases (E3) recruit ubiquitin-conjugate enzymes (E2) charged with ubiquitin (Ub) to catalyze ubiquitination. Non-covalent Ub binding to the backside of certain E2s promotes processive polyUb formation, but the mechanism remains elusive. Here, we show that backside bound Ub (UbB) enhances both RING-independent and RING-dependent UbcH5B-catalyzed donor Ub (UbD) transfer, but with a more prominent effect in RING-dependent transfer. UbB enhances RING E3s' affinities for UbcH5B-Ub, and RING E3-UbcH5B-Ub complex improves UbB's affinity for UbcH5B. A comparison of the crystal structures of a RING E3, RNF38, bound to UbcH5B-Ub in the absence and presence of UbB, together with molecular dynamics simulation and biochemical analyses, suggests UbB restricts the flexibility of UbcH5B's alpha1 and alpha1beta1 loop. UbB supports E3 function by stabilizing the RING E3-UbcH5B-Ub complex, thereby improving the catalytic efficiency of Ub transfer. Thus, UbB serves as an allosteric activator of RING E3-mediated Ub transfer. Activation of a Primed RING E3-E2-Ubiquitin Complex by Non-Covalent Ubiquitin.,Buetow L, Gabrielsen M, Anthony NG, Dou H, Patel A, Aitkenhead H, Sibbet GJ, Smith BO, Huang DT Mol Cell. 2015 Mar 18. pii: S1097-2765(15)00131-8. doi:, 10.1016/j.molcel.2015.02.017. PMID:25801170[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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