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Review
. 2008 Jun;9(6):536-42.
doi: 10.1038/embor.2008.93.

Atypical ubiquitin chains: new molecular signals. 'Protein Modifications: Beyond the Usual Suspects' review series

Fumiyo Ikeda  1 , Ivan Dikic
Affiliations
Review

Atypical ubiquitin chains: new molecular signals. 'Protein Modifications: Beyond the Usual Suspects' review series

Fumiyo Ikeda et al. EMBO Rep. 2008 Jun.

Abstract

Ubiquitin (Ub) is a small protein modifier that regulates many biological processes, including gene transcription, cell-cycle progression, DNA repair, apoptosis, virus budding and receptor endocytosis. Ub can be conjugated to _target proteins either as a monomer or as Ub chains that vary in length and linkage type. The various types of Ub modification are linked to distinct physiological functions in cells. MonoUb, for example, regulates DNA repair and receptor endocytosis, whereas lysine 48-linked Ub chains label proteins for proteasomal degradation. More recently, the importance of chains conjugated through the other six lysines in Ub, known as atypical Ub chains, has been revealed. Atypical chains can be homotypic, sequentially using the same lysine residue in Ub for conjugation; mixed-linkage, utilizing several distinct lysines to connect consecutive Ub moieties; or heterologous, connecting Ub with other Ub-like modifiers. Here, we describe recent progress in the understanding of atypical Ub chain assembly and their recognition by Ub-binding domains, and we discuss further their functional roles in vivo.

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Figures

Figure 1
Figure 1
A schematic model of possible ubiquitin chain formations on a _target protein. (A) Homotypic atypical and typical chains, such as lysine 6 (Lys 6)-, Lys 11-, Lys 27-, Lys 29-, Lys 33-, Lys 48- and Lys 63-linked ubiquitin (Ub) chains. (B) Mixed-linkage atypical chains are formed by the use of different lysines for sequential Ub conjugation, leading to the formation of bifurcated chains, for example, Lys 48/Lys 29 forks. (C) Heterologous chains are formed between Ub and ubiquitin-like proteins, for example the small ubiquitin-like modifier (SUMO) 2. (D) Multiple monoubiquitination moieties represent a subtype of multivalent chain-like Ub signals owing to the spatial organization of multiple monoUb molecules attached to the substrate.
Figure 2
Figure 2
Structural models indicating differences between Lys 48 and Lys 63 signals. (A) Lysine 48 (Lys 48)-linked di-ubiquitin (diUb; left panel) and Lys 63-linked diUb (right panel) show two different conformations, which indicate distinct binding properties for interaction with ubiquitin-binding domains (UBDs). Structures of other atypical chains have not yet been determined. (B) Conformational differences between alternatively linked polyubiquitin chains allow them to interact with UBDs in distinct binding modes: a sandwich-like mode (left panel) and as multiple independent UBD-binding sites (right panel). Shown here are structural models of the complexes of Lys 48- and Lys 63-linked diUb (left and right panels, respectively) with the UBA2 domain of HR23a. The distal and proximal Ubs are shown in surface representation, coloured light blue and green, respectively; the UBA domains are shown as ribbon. The hydrophobic patch residues (Leu 8–Ile 44–Val70) on the Ub surface are painted blue. (C) Lys 48-linked diUb can bind to UBDs at several binding sites, as observed in the case of the UBA domain of ubiquilin-1 (PLIC-1). UBA, ubiquitin-associated.
None
Fumiyo Ikeda
None
Ivan Dikic
None
See this image and copyright information in PMC

Comment in

  • Variations on complexity.
    Gannon F, Pariente N. Gannon F, et al. EMBO Rep. 2008 Jun;9(6):493. doi: 10.1038/embor.2008.85. EMBO Rep. 2008. PMID: 18516080 Free PMC article. No abstract available.

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