Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 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
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • In summary we describe here two proteins that

    2020-08-04

    In summary, we describe here two proteins that interact with the malin–laforin complex and modulate its ubiquitination activity. These new partners again highlight a link between proteins involved in LD and autophagy. Presumably, as we propose in Fig. 9, UBE2N interacts with the malin–laforin complex in order to promote the incorporation of K63-linked ubiquitin chains in the corresponding substrates. These chains would be recognized by p62, which would direct them to degradation via autophagy. This hypothesis would be in agreement with the previous observation that there is autophagy dysfunction in laforin- and malin-deficient mice (Aguado et al., 2010, Criado et al., 2012) and further corroborates the relevance of a functional malin–laforin complex in the maintenance of cellular protein homeostasis.
    Author contribution
    Acknowledgements We want to thank Dr. Manuel Rodriguez, Dr. Ch. Blattner, Dr. Jorge Moscat, Dr. Erwin Knecht and Dr. Peter Tontonoz for materials. This work has been supported by grants from the Spanish Ministry of Education and ScienceSAF2011-27442 and a grant from Generalitat Valenciana (PrometeoII/2014/029).
    Introduction Protein ubiquitination initiates with the ATP-dependent activation of ubiquitin (Ub) by ubiquitin-activating enzyme (E1), where a thioester linkage is formed between the C-terminus of ubiquitin and the active site cysteine (Cys) of E1 (Fig. 1). Ubiquitin is then transthiolated to the active site of one of ~40 different (in mammals) ubiquitin-conjugating Manumycin A synthesis (E2), generating an E2~Ub thioester. Specificity of ubiquitin modification is achieved largely through ubiquitin protein ligases (E3), which interact with both E2~Ub and the substrate to which ubiquitin is to be transferred. Ubiquitination generally occurs on primary amines as a consequence of nucleophilic attack on the E2~Ub linkage, resulting in stable isopeptide (or peptide) linkages with the C-terminus of ubiquitin. Ubiquitin can be transferred either to a lysine (Lys), or (less frequently) to the N-terminus, of either a substrate or another ubiquitin molecule to generate multi- or poly-ubiquitin chains. To a large extent, the nature of these ubiquitin linkages specifies the fate and function of the modified protein (see Fig. 1 and legend for more detail). E3s function by one of two general mechanisms. They serve either as catalytic intermediates in ubiquitination, akin to E1 and E2, or Multimeric protein mediate the transfer of ubiquitin directly from E2~Ub to substrate. The former mechanism is used by Homologous to E6-AP Carboxy Terminus (HECT)-type E3s (reviewed in this issue by Martin et al). The latter mechanism is a characteristic of Really Interesting New Gene (RING)-type E3s. RINGs coordinate two Zn ions in a cross-braced arrangement (Fig. 2 and described in detail below) to create a platform for binding of E2s. The RING-like U-box family of E3s adopts a similar structure to bind E2s but without employing Zn coordination. Together, RING (also known as RING finger, RING motif, or RING domain) and RING-like E3s (plant homeodomain/leukemia-associated protein (PHD/LAP) and U-box), collectively referred to as ‘RING-type’ in this review, constitute the large majority of the over 600 E3s in mammalian cells.