Structural Determinants of Ubiquitin-CXC Chemokine Receptor 4 Interaction

Saini, Vikas; Marchese, Adriano; Tang, Wei-Jen; Majetschak, Matthias

doi:10.1074/jbc.m111.298505

Cited by 39 publications

(56 citation statements)

References 48 publications

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“…Because it has been shown that SDF-1α is predominantly released from bone marrow stromal cells after AMD3100 administration, the finding that coadministration of ubiquitin plus AMD3100 did not influence the AMD3100-induced SDF-1α release in the present study could be explained by insufficient accumulation of ubiquitin in bone marrow (55). On the other hand, it cannot be excluded that ubiquitin functions as a partial or functionally selective CXCR4 agonist in vivo, which could correspond to recent findings suggesting that CXCR4 contains separate binding sites for SDF-1α and ubiquitin (13).…”

Section: Discussioncontrasting

confidence: 33%

“…Whereas SDF-1α is a CXCR4 and CXCR7 agonist, ubiquitin is a CXCR4 agonist, but does not bind to CXCR7 (12,13,15,61). Besides being a CXCR4 antagonist, AMD3100 is also a CXCR7 ligand with weak allosteric agonist activity and increases binding of SDF-1α to CXCR7 (62).…”

Section: Discussionmentioning

confidence: 99%

“…It also plays pleiotropic roles in the immune system and during tissue repair processes and gained particular attention as a drug target because of its role in human immunodeficiency virus (HIV) infection and metastatic diseases (2)(3)(4)(5)(6)(7)(8)(9)(10). Although the constitutively expressed chemokine stromal cell-derived factor (SDF)-1α is the cognate ligand of CXCR4 (11), we recently identified extracellular ubiquitin as another natural CXCR4 agonist (12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

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Initial Assessment of the Role of CXC Chemokine Receptor 4 after Polytrauma

Bach

Saini

Baker

et al. 2012

Mol Med

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CXC chemokine receptor (CXCR)-4 agonists have been shown to attenuate inflammation and organ injury in various disease models, including trauma/hemorrhage. The pathophysiological role of CXCR4 during the early response to tissue injury, however, remains unknown. Therefore, we investigated the effects of AMD3100, a drug that antagonizes binding of stromal cell-derived factor (SDF)-1α and ubiquitin to CXCR4 during the initial response to polytrauma in pigs. Fifteen minutes before polytrauma (femur fractures/lung contusion; control: sham), 350 nmol/kg AMD3100, equimolar AMD3100 and ubiquitin (350 nmol/kg each) or vehicle were administered intravenously. After a 60-min shock period, fluid resuscitation was performed for 360 min. Ubiquitin binding to peripheral blood mononuclear cells was significantly reduced after intravenous AMD3100. SDF-1α plasma levels increased transiently >10-fold with AMD3100 in all animals. In injured animals, AMD3100 increased fluid requirements to maintain hemodynamics and enhanced increases in peripheral blood granulocytes, lymphocytes and monocytes, compared with its effects in uninjured animals. Cytokine release from leukocytes in response to Toll-like receptor (TLR)-2 and TLR-4 activation was increased after in vitro AMD3100 treatment of normal whole blood and after in vivo AMD3100 administration in animals subjected to polytrauma. Coadministration of AMD3100/ubiquitin reduced lactate levels, prevented AMD3100-induced increases in fluid requirements and sensitization of the tumor necrosis factor (TNF)-α and interleukin (IL)-6 release upon TLR-2/4 activation, but did not attenuate increases in leukocyte counts and SDF-1α plasma levels. Our findings suggest that CXCR4 controls leukocyte mobilization after trauma, regulates leukocyte reactivity toward inflammatory stimuli and mediates protective effects during the early phase of trauma-induced inflammation.

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Section: Discussioncontrasting

confidence: 33%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Initial Assessment of the Role of CXC Chemokine Receptor 4 after Polytrauma

Bach

Saini

Baker

et al. 2012

Mol Med

Self Cite

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“…Thus, we tested the effect of CSB6B in the extracellular space. It has been explored that the extracellular ubiquitin binds to CXCR4 as a ligand and turns on CXCR4 signaling, which results in enhanced AKT expression, AKT phosphorylation, and metastasis [13,31]. In the ubiquitin-CXCR4 signaling process, it is known that hydrophobic residues of ubiquitin including Phe4 and Val70 directly bind CXCR4, and the C-terminal motif facilitates receptor activation [31].…”

Section: Resultsmentioning

confidence: 99%

An ubiquitin-binding molecule can work as an inhibitor of ubiquitin processing enzymes and ubiquitin receptors

Nguyen

Ghosh

et al. 2016

Biochemical and Biophysical Research Communications

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The ubiquitin pathway plays a critical role in regulating diverse biological processes, and its dysregulation is associated with various diseases. Therefore, it is important to have a tool that can control the ubiquitin pathway in order to improve understanding of this pathway and to develop therapeutics against relevant diseases. We found that Chicago Sky Blue 6B binds directly to the β-groove, a major interacting surface of ubiquitin. Hence, it could successfully inhibit the enzymatic activity of ubiquitin processing enzymes and the binding of ubiquitin to the CXCR4, a cell surface ubiquitin receptor. Furthermore, we demonstrated that this ubiquitin binding chemical could effectively suppress the ubiquitin induced cancer cell migration by blocking ubiquitin-CXCR4 interaction. Current results suggest that ubiquitin binding molecules can be developed as inhibitors of ubiquitin-protein interactions, which will have the value not only in unveiling the biological role of ubiquitin but also in treating related diseases.

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“…3) that accompanies the separation into (at least) two topological moieties, suggesting that separate receptor docking and effector sites are highly likely on this molecule, thus resembling the structure-function relationships generally observed with chemokines (Saini et al, 2011). Such observations have been made earlier with other CAP proteins of nematodes (Asojo et al, 2005b, Osman et al, 2012, and support the notion that these parasite molecules may act as agonists or ligands for GPCRs such as chemokine receptors, similar to snake and bee toxins that also belong to the CAP superfamily (e.g.…”

Section: Structure Modelsmentioning

confidence: 95%

The barber's pole worm CAP protein superfamily — A basis for fundamental discovery and biotechnology advances

Mohandas

Young

Jabbar

et al. 2015

Biotechnology Advances

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Parasitic worm proteins that belong to the cysteine-rich secretory proteins, antigen 5 and pathogenesis-related 1 (CAP) superfamily are proposed to play key roles in the infection process and the modulation of immune responses in host animals. However, there is limited information on these proteins for most socio-economically important worms. Here, we review the CAP protein superfamily of Haemonchus contortus (barber's pole worm), a highly significant parasitic roundworm (order Strongylida) of small ruminants. To do this, we mined genome and transcriptomic datasets, predicted and curated full-length amino acid sequences (n = 45), undertook systematic phylogenetic analyses of these data and investigated transcription throughout the life cycle of H. contortus. We inferred functions for selected C. elegans orthologs (including vap-1, vap-2, scl-5 and lon-1) based on genetic networking and by integrating data and published information, and were able to infer that a subset of orthologs and their interaction partners play pivotal roles in growth and development via the insulin-like and/or the TGF-beta signaling pathways. The identification of the important and conserved growth regulator LON-1 led us to appraise the threedimensional structure of this CAP protein by comparative modelling. This model revealed the presence of different topological moieties on the canonical fold of the CAP domain, which coincide with an overall charge separation as indicated by the electrostatic surface potential map. These observations suggest the existence of separate sites for effector binding and receptor interactions, and thus support the proposal that these worm molecules act in similar ways as venoms act as ligands for chemokine receptors or G protein-coupled receptor effectors. In conclusion, this review should guide future molecular studies of these molecules, and could support the development of novel interventions against haemonchosis.

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Structural Determinants of Ubiquitin-CXC Chemokine Receptor 4 Interaction

Cited by 39 publications

References 48 publications

Initial Assessment of the Role of CXC Chemokine Receptor 4 after Polytrauma

Initial Assessment of the Role of CXC Chemokine Receptor 4 after Polytrauma

An ubiquitin-binding molecule can work as an inhibitor of ubiquitin processing enzymes and ubiquitin receptors

The barber's pole worm CAP protein superfamily — A basis for fundamental discovery and biotechnology advances

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