The DNA Damage-Inducible UbL-UbA Protein Ddi1 Participates in Mec1-Mediated Degradation of Ho Endonuclease

Kaplun, Ludmila; Tzirkin, Regina; Bakhrat, Anya; Shabek, Nitzan; Ivantsiv, Yelena; Raveh, Dina

doi:10.1128/mcb.25.13.5355-5362.2005

Cited by 94 publications

(137 citation statements)

References 71 publications

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“…The UbL domain of Ddi1 is required for interaction with the 19S RP of the proteasome, and one model for activation of an UbL-UbA protein could be that binding of a K48-linked ubiquitin chain to the UbA domain frees the UbL domain to bind the proteasome. This model is suggested by our finding that Ddi1 can bind ubiquitylated Ho in the absence of its UbL domain (23). Furthermore, the UbL of Rad23 interacts with its UbA domain, and this may represent an inactive form of the protein (37).…”

Section: Discussionmentioning

confidence: 63%

“…Therefore, deletion of the Ufo1 UIMs may be interfering with a function downstream of ubiquitylation. We recently found that the ubiquitin domain protein Ddi1 is required for the final stages of degradation of Ho and that, in the absence of Ddi1, Ho accumulates in a stable ubiquitylated form (23). Ddi1 belongs to a family of UbL-UbA proteins proposed to act as proteasome receptors for ubiquitylated substrates (11,35).…”

Section: Resultsmentioning

confidence: 99%

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Unique Role for the UbL-UbA Protein Ddi1 in Turnover of SCF^Ufo1 Complexes

Ivantsiv

Kaplun

Tzirkin-Goldin

et al. 2006

Molecular and Cellular Biology

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SCF complexes are E3 ubiquitin-protein ligases that mediate degradation of regulatory and signaling proteins and control G 1 /S cell cycle progression by degradation of G 1 cyclins and the cyclin-dependent kinase inhibitor, Sic1. Interchangeable F-box proteins bind the core SCF components; each recruits a specific subset of substrates for ubiquitylation. The F-box proteins themselves are rapidly turned over by autoubiquitylation, allowing rapid recycling of SCF complexes. Here we report a role for the UbL-UbA protein Ddi1 in the turnover of the F-box protein, Ufo1. Ufo1 is unique among F-box proteins in having a domain comprising multiple ubiquitin-interacting motifs (UIMs) that mediate its turnover. Deleting the UIMs leads to stabilization of Ufo1 and to cell cycle arrest at G 1 /S of cells with long buds resembling skp1 mutants. Cells accumulate substrates of other F-box proteins, indicating that the SCF pathway of substrate ubiquitylation is inhibited. Ufo1 interacts with Ddi1 via its UIMs, and ⌬ddi1 cells arrest when full-length UFO1 is overexpressed. These results imply a role for the UIMs in turnover of SCF Ufo1 complexes that is dependent on Ddi1, a novel activity for an UbL-UbA protein.

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Section: Discussionmentioning

confidence: 63%

Section: Resultsmentioning

confidence: 99%

Unique Role for the UbL-UbA Protein Ddi1 in Turnover of SCF^Ufo1 Complexes

Ivantsiv

Kaplun

Tzirkin-Goldin

et al. 2006

Molecular and Cellular Biology

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“…8D). This mechanism would resemble the classical cooperation of a UBL domain with its closely related homolog, the ubiquitin-associated (UBA) domain, which act as a carrier to deliver ubiquitylated substrates to the proteasome (Kaplun et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

The structure of the TBCE/TBCB chaperones and α-tubulin complex shows a tubulin dimer dissociation mechanism

Serna

Carranza

Martín‐Benito

et al. 2015

Journal of Cell Science

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BSTRACTTubulin proteostasis is regulated by a group of molecular chaperones termed tubulin cofactors (TBC). Whereas tubulin heterodimer formation is well-characterized biochemically, its dissociation pathway is not clearly understood. Here, we carried out biochemical assays to dissect the role of the human TBCE and TBCB chaperones in a-tubulin-b-tubulin dissociation. We used electron microscopy and image processing to determine the threedimensional structure of the human TBCE, TBCB and a-tubulin (aEB) complex, which is formed upon a-tubulin-b-tubulin heterodimer dissociation by the two chaperones. Docking the atomic structures of domains of these proteins, including the TBCE UBL domain, as we determined by X-ray crystallography, allowed description of the molecular architecture of the aEB complex. We found that heterodimer dissociation is an energy-independent process that takes place through a disruption of the a-tubulin-b-tubulin interface that is caused by a steric interaction between b-tubulin and the TBCE cytoskeleton-associated protein glycine-rich (CAP-Gly) and leucinerich repeat (LRR) domains. The protruding arrangement of chaperone ubiquitin-like (UBL) domains in the aEB complex suggests that there is a direct interaction of this complex with the proteasome, thus mediating a-tubulin degradation.

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“…Rub1 Binds to Non-proteasomal Ub Receptors/ShuttlesThere are three well-studied non-proteasomal Ub receptors/ shuttles: Rad23 (its human orthologue is known as hHR23a) (47,48), Dsk2 (known as hPLIC1 or Ubiquilin 1 (UQ1) in humans) (49), and Ddi1 1 (50,51). All of them are unique in that they contain an N-terminal Ub-like (UBL) domain that binds to the proteasome via Rpn1 (42,52,53) and a C-terminal Ubassociated (UBA) domain that binds to Ub chains (54,55).…”

Section: Rub1 Is Structurally Similar To Ubiquitin-although Rub1 Ismentioning

confidence: 99%

Recognition and Cleavage of Related to Ubiquitin 1 (Rub1) and Rub1-Ubiquitin Chains by Components of the Ubiquitin-Proteasome System

Singh

Zerath

Kleifeld

et al. 2012

Molecular & Cellular Proteomics

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Of all ubiquitin-like proteins, Rub1 (Nedd8 in mammals) is the closest kin of ubiquitin. We show via NMR that structurally, Rub1 and ubiquitin are fundamentally similar as well. Despite these profound similarities, the prevalence of Rub1/Nedd8 and of ubiquitin as modifiers of the proteome is starkly different, and their attachments to specific substrates perform different functions. Recently, some proteins, including p53, p73, EGFR, caspase-7, and Parkin, have been shown to be modified by both Rub1/ Nedd8 and ubiquitin within cells. To understand whether and how it might be possible to distinguish among the same target protein modified by Rub1 or ubiquitin or both, we examined whether ubiquitin receptors can differentiate between Rub1 and ubiquitin. Surprisingly, Rub1 interacts with proteasome ubiquitin-shuttle proteins comparably to ubiquitin but binds more weakly to a proteasomal ubiquitin receptor Rpn10. We identified Rub1-ubiquitin heteromers in yeast and Nedd8-Ub heteromers in human cells. We validate that in human cells and in vitro, human Rub1 (Nedd8) forms chains with ubiquitin where it acts as a chain terminator. Interestingly, enzymatically assembled K48-linked Rub1-ubiquitin heterodimers are recognized by various proteasomal ubiquitin shuttles and receptors comparably to K48-linked ubiquitin homodimers. Furthermore, these heterologous chains are cleaved by COP9 signalosome or 26S proteasome. A derubylation function of the proteasome expands the repertoire of its enzymatic activities. In contrast, Rub1 conjugates may be somewhat resilient to the actions of other canonical deubiquitinating enzymes. Taken together, these findings suggest that once Rub1/Nedd8 is channeled into ubiquitin pathways, it is recognized essentially like The selective degradation of many proteins in eukaryotic cells is a highly specific and irreversible process required to perform vital cellular functions such as cell cycle progression (1, 2), differentiation and development (3, 4), and transcriptional control (5). One of the major pathways involved in this selective degradation is the ubiquitin-proteasome pathway. In this pathway, ubiquitin (Ub), a 76-amino-acid protein, is attached to the substrate, and this is followed by the recognition and degradation of the substrate by a protein complex collectively known as proteasome (6 -8).The attachment of Ub (ubiquitination) to a substrate protein is achieved via a cascade of enzymatic reactions (involving E1, E2, and E3 enzymes) that results in the formation of an isopeptide bond between the C-terminal glycine of Ub and a lysine residue of the substrate (9 -11). Sequential repetition of this cascade can result in the attachment of a chain of Ub molecules (polyubiquitin) to the substrate protein. The length and topology of the polyubiquitin (polyUb) tag decide the fate of the substrate protein. For example, we and others have shown that a K48-linked tetraubiquitin (tetraUb) chain that acts as a proteasomal degradation signal forms a "closed" structure (12, 13), whereas a K63-linked Ub...

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The DNA Damage-Inducible UbL-UbA Protein Ddi1 Participates in Mec1-Mediated Degradation of Ho Endonuclease

Cited by 94 publications

References 71 publications

Unique Role for the UbL-UbA Protein Ddi1 in Turnover of SCF^Ufo1 Complexes

Unique Role for the UbL-UbA Protein Ddi1 in Turnover of SCF^Ufo1 Complexes

The structure of the TBCE/TBCB chaperones and α-tubulin complex shows a tubulin dimer dissociation mechanism

Recognition and Cleavage of Related to Ubiquitin 1 (Rub1) and Rub1-Ubiquitin Chains by Components of the Ubiquitin-Proteasome System

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The DNA Damage-Inducible UbL-UbA Protein Ddi1 Participates in Mec1-Mediated Degradation of Ho Endonuclease

Cited by 94 publications

References 71 publications

Unique Role for the UbL-UbA Protein Ddi1 in Turnover of SCFUfo1 Complexes

Unique Role for the UbL-UbA Protein Ddi1 in Turnover of SCFUfo1 Complexes

The structure of the TBCE/TBCB chaperones and α-tubulin complex shows a tubulin dimer dissociation mechanism

Recognition and Cleavage of Related to Ubiquitin 1 (Rub1) and Rub1-Ubiquitin Chains by Components of the Ubiquitin-Proteasome System

Contact Info

Product

Resources

About

Unique Role for the UbL-UbA Protein Ddi1 in Turnover of SCF^Ufo1 Complexes

Unique Role for the UbL-UbA Protein Ddi1 in Turnover of SCF^Ufo1 Complexes