Solution structure of the N‐terminal domain of DC‐UbP/UBTD2 and its interaction with ubiquitin

Song, Ai-Xin; Zhou, Chengyu; Guan, Xiao; Sze, Kong-Hung; Hu, Hongyu

doi:10.1002/pro.386

Cited by 7 publications

(9 citation statements)

References 27 publications

(16 reference statements)

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“…The ubiquitin domain and ubiquitin-like domain binding proteins are potentially very important in regulating the ubiquitin-proteosome pathway that is involved in post-translational regulation of various proteins [25][26][27][28][29]. UBTD1 and UBTD2 are both ubiquitin domain-containing proteins [29] and UBTD2 can potentially regulate the stability of proteins involved in various physiological processes relevant to many disease phenotypes, such as ageing and cancer. Cellular senescence is believed to play a role in cancer and age-associated pathologies [30].…”

Section: Discussionmentioning

confidence: 99%

UBTD1 induces cellular senescence through an UBTD1-Mdm2/p53 positive feedback loop

Zhang

Wang

et al. 2015

J. Pathol.

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The tumour suppressor p53 plays an important role in tumourigenesis. Besides inducing apoptosis, it regulates cellular senescence, which constitutes an important barrier to tumourigenesis. The mechanism of regulation of cellular senescence by p53 and its downstream pathway are poorly understood. Here, we report that the ubiquitin domain-containing 1 (UBTD1) gene, a new downstream target of p53, induces cellular senescence and acts as a novel tumour suppressor by a mechanism that depends on p53. Expression of UBTD1 increased upon cellular senescence induced by serial passageing of cultures, as well as by exposure to DNA-damageing drugs that induce premature senescence. Over-expression of UBTD1 induces senescence in human fibroblasts and cancer cells and attenuation of the transformed phenotype in cancer cells. UBTD1 is down-regulated in gastric and colorectal cancer tissues, and its lower expression correlates with a more aggressive phenotype and worse prognosis. Multivariate analysis revealed that UBTD1 expression was an independent prognostic factor for gastric cancer patients. Furthermore, UBTD1 increased the stability of p53 protein, by promoting the degradation of Mdm2 protein. Importantly, UBTD1 and p53 function mutually depend on each other in regulating cellular senescence and proliferation. Thus, our data suggest that, upon DNA damage, p53 induction by UBTD1 creates a positive feedback mechanism to further increase p53 expression. Our results establish UBTD1 as a regulator of cellular senescence that mediates p53 function, and provide insights into the mechanism of Mdm2 inhibition that impacts p53 dynamics during cellular senescence and tumourigenesis.

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Section: Discussionmentioning

confidence: 99%

UBTD1 induces cellular senescence through an UBTD1-Mdm2/p53 positive feedback loop

Zhang

Wang

et al. 2015

J. Pathol.

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“…Many other structural folds have evolved ubiquitin-binding surfaces. In the past year, novel UBD structural folds have been described in the N-terminal domain of DC-UbP (111), WD40 beta-propellers (112), and MDA-9/syntenin (113). DC-UbP’s N-terminal ubiquitin-binding domain forms an alpha-alpha-alpha-betabeta pattern with a short C-terminal alpha-helix (111).…”

Section: Ubiquitin-binding Domains (Ubds)mentioning

confidence: 99%

“…In the past year, novel UBD structural folds have been described in the N-terminal domain of DC-UbP (111), WD40 beta-propellers (112), and MDA-9/syntenin (113). DC-UbP’s N-terminal ubiquitin-binding domain forms an alpha-alpha-alpha-betabeta pattern with a short C-terminal alpha-helix (111). It binds to ubiquitin’s hydrophobic patch and C-terminal residues (Leu71, Arg72, and Leu72) by using amino acids from the alpha1-alpha2 loop, alpha2, alpha3, and the beta1beta2 loop (111).…”

Section: Ubiquitin-binding Domains (Ubds)mentioning

confidence: 99%

“…DC-UbP’s N-terminal ubiquitin-binding domain forms an alpha-alpha-alpha-betabeta pattern with a short C-terminal alpha-helix (111). It binds to ubiquitin’s hydrophobic patch and C-terminal residues (Leu71, Arg72, and Leu72) by using amino acids from the alpha1-alpha2 loop, alpha2, alpha3, and the beta1beta2 loop (111). The C-terminal region of DC-UbP contains a UBL domain (114), thereby linking it to the UBL-UBA family of proteins, which include hHR23 and hPLIC, discussed in Section 4.1.1.…”

Section: Ubiquitin-binding Domains (Ubds)mentioning

confidence: 99%

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Ubiquitin and its binding domains

Randles

Walters²

2012

Front Biosci

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Post-translational modification by ubiquitin (ubiquitination, ubiquitylation, ubiquitinylation) is used as a robust signaling mechanism in a variety of processes that are essential for cell homeostasis. Its signaling specificity is conferred by the inherent dynamics of ubiquitin, the multivalency of ubiquitin chains, and its subcellular context, often defined by ubiquitin receptors and the substrate. Greater than 150 ubiquitin receptors have been found and their ubiquitin-binding domains (UBDs) are structurally diverse and include alpha-helical motifs, zinc fingers (ZnF), pleckstrin-homology (PH) domains, ubiquitin conjugating (Ubc)-related structures and src homology 3 (SH3) domains. New UBD structural motifs continue to be identified expanding the ubiquitin-signaling map to proteins and structural families not previously associated with ubiquitin trafficking. In this manuscript, we highlight several ubiquitin receptors from the multiple UBD folds with a focus on the structural characteristics of their interaction with ubiquitin.

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“…The UbL structure also displays a positively-charged surface distinct from Ub molecule, suggesting that the UbL domain of DC-UbP may have its unique interacting partner and cellular function. We also solved the novel structure of the N-terminal part of DC-UbP (UbP_N) and found that it is potentially a Ub-binding domain (UBD) [14] . More importantly, the DC-UbP protein is a combination of UbL and UBD domains, which increase the possibility for DC-UbP to be involved in the ubiquitination process or other relevant pathways [15] .…”

Section: Introductionmentioning

confidence: 99%

A Ubiquitin Shuttle DC-UbP/UBTD2 Reconciles Protein Ubiquitination and Deubiquitination via Linking UbE1 and USP5 Enzymes

Song

Gao

et al. 2014

PLoS ONE

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The ubiquitination levels of protein substrates in eukaryotic cells are delicately orchestrated by various protein cofactors and enzymes. Dendritic cell-derived ubiquitin (Ub)-like protein (DC-UbP), also named as Ub domain-containing protein 2 (UBTD2), is a potential Ub shuttle protein comprised of a Ub-like (UbL) domain and a Ub-binding domain (UBD), but its biological function remains largely unknown. We identified two Ub-related enzymes, the deubiquitinating enzyme USP5 and the Ub-activating enzyme UbE1, as interacting partners of DC-UbP from HEK 293T cells. Biochemical studies revealed that the tandem UBA domains of USP5 and the C-terminal Ub-fold domain (UFD) of UbE1 directly interacted with the C-terminal UbL domain of DC-UbP but on the distinct surfaces. Overexpression of DC-UbP in HEK 293T cells enhanced the association of these two enzymes and thus prompted cellular ubiquitination, whereas knockdown of the protein reduced the cellular ubiquitination level. Together, DC-UbP may integrate the functions of USP5 and UbE1 through interacting with them, and thus reconcile the cellular ubiquitination and deubiquitination processes.

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Solution structure of the N‐terminal domain of DC‐UbP/UBTD2 and its interaction with ubiquitin

Cited by 7 publications

References 27 publications

UBTD1 induces cellular senescence through an UBTD1-Mdm2/p53 positive feedback loop

UBTD1 induces cellular senescence through an UBTD1-Mdm2/p53 positive feedback loop

Ubiquitin and its binding domains

A Ubiquitin Shuttle DC-UbP/UBTD2 Reconciles Protein Ubiquitination and Deubiquitination via Linking UbE1 and USP5 Enzymes

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