Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05

    • Mutation of RING type E s or

    2020-07-30

    Mutation of RING-type E3s, or modulation of their activity in other ways, is often associated with human disease. BRCA1, an E3 that plays critical roles in DNA repair, is mutated in familial breast and ovarian cancers [2]. Mutations in components of the FANC ubiquitin ligase, also involved in DNA repair, result in the multisystemic Fanconi anemia syndrome [3], which includes severe developmental defects and, in children who survive, there is a marked increased risk of tumor development. Mdm2 (or Hdm2 in humans) was first characterized as a genetic amplification in mice associated with malignancy [4]. Indeed, increased activity of this E3 towards the tumor suppressor p53, either through increased Mdm2 expression or loss of a negative modulator of Mdm2 activity, is associated with human cancers, particularly those 50% that retain wild type p53 [5]. The F-box protein FBXO11, the substrate recognition component of the multi-subunit SCFFBXO11 E3 (see Section 3 below), functions as a tumor suppressor by targeting BCL6, a transcription factor involved in B-cell differentiation and activation, for degradation [6]. FBXO11 is mutated or deleted in diffuse large B-cell lymphomas [6]. Mutations in VHL, the substrate recognition component of the CRL2VHL E3, lead to the malignant von Hippel–Lindau syndrome, which presumably arises because of dysregulation of HIF1-α and/or HIF2-α [5]. Mutations in the RING–IBR (in between RING)–RING E3 Parkin are associated with autosomal recessive juvenile Parkinsonism (AR-JP) [7]. Additionally, a number of viruses, for example, herpes simplex virus type 1 (HSV-1), encode RING-type E3s as virulence factors [8], [9]. In the case of HIV, the virus encodes an adaptor protein, Vpu, that redirects SCFβTrCP to downregulate CD4 [10]. The importance of RING-type E3s to human health and disease has contributed to their becoming an intensively-studied family of proteins. This review will provide an overview of their regulated function and structure and recent advances in understanding how they mediate ubiquitination by E2s.
    RING dimerization RING-type domains are found in many different structural contexts. While many exist as single-chain Glimepiride mg (Fig. 3A), a notable feature of RING-type E3s is their tendency to form homodimers and heterodimers (Fig. 3C–F). Homodimeric RING-type E3s include cIAP, RNF4, BIRC7 (shown in Fig. 3D), IDOL, and the U-box proteins CHIP and Prp19 [11], [12], [13], [14], [15], [16], [17]. Examples of well-characterized heterodimeric E3s include BRCA1–BARD1 (shown in Fig. 3F), Mdm2–MdmX (or HdmX/Hdm4 in humans), and RING1B–Bmi1. While for homodimeric RING E3s both RINGs have the intrinsic capacity to functionally interact with E2s, this appears not to be the case for some heterodimeric RINGs. BRCA1 and RING1B each function with E2, while their partners serve to enhance activity, potentially interact with substrates, and, in the case of BRCA1–BARD1, to stabilize the complex in vivo[18], [19], [20], [21]. For the RING of BARD1, its lack of E2 binding activity can be attributed, at least in part, to the absence of a portion of the conserved central α-helix necessary for E2 interactions [19], [22]. In contrast, there is evidence that MdmX, the ‘inactive’ partner, does physically interact with E2, in addition to having the capacity to bind the best-characterized Mdm2–MdmX substrate, p53. Importantly, while Mdm2 can homodimerize and is active, MdmX has little tendency to form a homodimer and is inactive, and the two RINGs can form an active heterodimer [23], [24]. This underscores the important role played by RING dimerization (discussed further below). Strikingly, MdmX\'s lack of in vitro activity can be restored by mutating a single residue at the RING dimerization interface to that found in the analogous position of Mdm2 [25]. However, additional mutations of MdmX to mimic the nucleolar localization sequence of Mdm2, found in its RING:E2 interface, are required for in vivo activity of MdmX towards p53 [25]. Interestingly, since p53 exists largely as a homo-tetramer [26], there is the potential to assemble four Mdm2–MdmX heterodimers in close proximity. RING dimerization may also be a mode of cellular regulation of ubiquitination, as occurs for cIAP1, where its RING homodimerization interface is sequestered in a ‘closed’ inactive form until activation by IAP antagonists, such as SMAC (second mitochondrial activator of caspases) or DIABLO (direct IAP-binding protein with low isoelectric point) [27]. Binding of SMAC or DIABLO to cIAP stabilizes it in an ‘open’ conformation that allows RING dimerization and thus, presumably, E2 binding and ubiquitin transfer.