Molecular Mechanism of CCAAT-Enhancer Binding Protein Recruitment by the TRIB1 Pseudokinase

Murphy, James M.; Nakatani, Yoshio; Jamieson, Sam A.; Dai, Wayne Wei-Ming; Lucet, Isabelle S; Mace, Peter D.

doi:10.1016/j.str.2015.08.017

Cited by 100 publications

(170 citation statements)

References 64 publications

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“…Remarkably, the isolated Trib1 peptide has a stronger IC 50 in the competition assay than a Trib1 molecule containing residues 83-372 (Figure 4B). This result is consistent with a recent structure of Trib1 in which the COP1-interacting motif engages in intramolecular interactions with the adjacent pseudokinase domain (Murphy et al, 2015). …”

Section: Resultssupporting

confidence: 92%

“…Instead, current evidence suggests that Tribbles serves to alter COP1 substrate specificity by directing the activity of COP1 toward C/EBPα (Keeshan et al, 2006). A structure of the human Trib1 pseudokinase domain containing the C-terminal COP1 binding peptide, recently published by Murphy and colleagues, shows the C-terminal COP1-binding site tethered to the N-lobe of the Trib1 pseudokinase domain, suggesting that the molecule normally adopts a conformation in which the COP1-binding motif is masked by autoinhibitory interactions with the kinase-homology domain (Murphy et al, 2015). We thus propose the following model for the molecular mechanism of degradation of and other targets by COP1-Trib1 complexes (Figure 6).…”

Section: Discussionmentioning

confidence: 99%

“…In this model, forced expression of either Trib1 or Trib2, each of which is a homologue of Drosophila tribbles, gives rise to AML with high penetrance. Tumor formation in this context relies on the integrity of a COP1 binding motif near the Trib C-terminus, recently shown to be held tethered to the N-lobe of Trib1 in the absence of COP1 (Murphy et al, 2015). Additional studies probing the molecular mechanism of leukemogenesis show that COP1 does not efficiently degrade Trib1 or Trib2.…”

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confidence: 99%

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Structural Basis for Substrate Selectivity of the E3 Ligase COP1

et al. 2016

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Summary COP1 proteins are E3 ubiquitin ligases that regulate phototropism in plants and target transcription factors for degradation in mammals. The substrate-binding region of COP1 resides within a WD40-repeat domain that also binds to Trib proteins, which are adaptors for C/EBPα degradation. We report here structures of the human COP1 WD40 domain in isolation, and complexes of the human and Arabidopsis thaliana COP1 WD40 domains with the binding motif of Trib1. The human and Arabidopsis WD40 domains are seven-bladed β-propellers with an inserted loop on the bottom face of the first blade. The Trib1 peptide binds in an extended conformation to a highly conserved surface on the top face of the β-propeller, indicating a general mode for recognition of peptide motifs by COP1. Together, these studies identify the structural basis and key interactions for motif recognition by COP1, and hint at how Trib1 autoinhibition is overcome to target C/EBPα for degradation.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Structural Basis for Substrate Selectivity of the E3 Ligase COP1

et al. 2016

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“…SAXS data collection was performed at the Australian Synchrotron SAXS/WAXS beamline using an inline gel filtration chromatography setup (67), essentially as described previously (68)(69)(70)(71). Summary statistics for data collection and analysis are reported in Table 2.…”

Section: Methodsmentioning

confidence: 99%

Structural basis of autoregulatory scaffolding by apoptosis signal-regulating kinase 1

Weijman

Kumar

Jamieson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Apoptosis signal-regulating kinases (ASK1-3) are apical kinases of the p38 and JNK MAP kinase pathways. They are activated by diverse stress stimuli, including reactive oxygen species, cytokines, and osmotic stress; however, a molecular understanding of how ASK proteins are controlled remains obscure. Here, we report a biochemical analysis of the ASK1 kinase domain in conjunction with its N-terminal thioredoxin-binding domain, along with a central regulatory region that links the two. We show that in solution the central regulatory region mediates a compact arrangement of the kinase and thioredoxin-binding domains and the central regulatory region actively primes MKK6, a key ASK1 substrate, for phosphorylation. The crystal structure of the central regulatory region reveals an unusually compact tetratricopeptide repeat (TPR) region capped by a cryptic pleckstrin homology domain. Biochemical assays show that both a conserved surface on the pleckstrin homology domain and an intact TPR region are required for ASK1 activity. We propose a model in which the central regulatory region promotes ASK1 activity via its pleckstrin homology domain but also facilitates ASK1 autoinhibition by bringing the thioredoxin-binding and kinase domains into close proximity. Such an architecture provides a mechanism for control of ASK-type kinases by diverse activators and inhibitors and demonstrates an unexpected level of autoregulatory scaffolding in mammalian stress-activated MAP kinase signaling.itogen-activated protein (MAP) kinase cascades transmit signals from membrane-associated receptors to intracellular targets to effect changes in cellular behavior. They form a hierarchical system in which activated upstream kinases (MAP3Ks) phosphorylate intermediate MAP kinase kinases (MAP2Ks), which in turn phosphorylate terminal MAP kinases, primarily ERK, p38, and JNK and their isoforms (1). Extensive studies have focused on the activation of RAS-RAF-MEK upstream in the ERK pathway and provided fertile ground for the discovery of new therapeutics (2). In contrast to the ERK pathway, which primarily promotes cellular proliferation, JNK and p38 phosphorylate a range of substrates to promote inflammation and cell death (1, 3). In addition, cross-regulation among the p38, JNK, and ERK pathways is important for the efficacy of various cancer therapies that are in use or in development (4, 5). Molecular details on the more diverse upstream regulation of the p38 and JNK pathways are currently less clear, however.Apoptosis signal-regulating kinases (ASK1-3) are MAP3Ks that trigger cellular responses to redox stress and inflammatory cytokines (6, 7) and play vital roles in innate immunity and viral infection (8-11). When activated, ASK1-3 activate JNK and p38 via phosphorylation of MAP2Ks (MKK3/4/6/7) (12). The key initiator role of ASK1-3 in this pathway means that either too much or too little ASK activity can have pathological effects. For instance, inhibiting ASK1 is beneficial against gastric cancer (13,14), but inactivating mutations in ASK1...

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“…However, key differences between TRIB family members are important when considering their therapeutic targeting in leukemia. TRIB pseudokinases are classified based on sequence homology as serine/threonine pseudokinases that either lack (TRIB1), or exhibit low (TRIB2 and TRIB3) vestigial ATP affinity and phosphotransferase capacity (Bailey et al, 2015, Murphy et al, 2015. In addition, TRIB1 and TRIB2 are more similar (possessing a sequence homology of ~71%) compared to the most recently evolved family member TRIB3 (Eyers et al, 2017), whose homology with both TRIB1 and TRIB2 is only ~55%, suggesting mechanistic and functional divergence.…”

mentioning

confidence: 99%

The Tribble with APL: A New Road to Therapy

Carmody

Keeshan

2017

Cancer Cell

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SummaryThe t(15;17) translocation generates a PML-RARα fusion protein causative for acute promyelocytic leukemia (APL). Li et al. identify the pseudokinase stress protein TRIB3 as an important factor in APL disease progression and therapy resistance. Targeting the interaction of TRIB3 and PML-RARα using peptide technology provides a novel therapeutic approach. Main TextAcute promyelocytic leukemia (APL) is a distinct subtype (5-15%) of acute myeloid leukemia (AML) characterized by a t(15:17) chromosomal translocation in myeloid precursor cells, leading to the expression of the PML-RARα oncofusion gene. PML-RARα expression blocks promyelocyte differentiation leading to the proliferation of leukemia blasts. The molecular basis for the effects of PML-RARα lies in its activity as a constitutive repressor of RARα and RXR target genes and in its dominant negative effects on PML, a protein that is necessary for the formation of nuclear bodies that have extensive influence on the activity of many transcription factors, including p53. Current therapies for APL include treatment with pharmacological doses of all-trans-retinoic-acid (ATRA) and arsenic trioxide (As2O3), both of which lead to the SUMOylation and ubiquitination dependent degradation of PML-RARα, and APL cell differentiation. These treatments are effective with ~75% of patients cured of the disease, however therapy resistance and disease relapse remains an unmet clinical need.

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Molecular Mechanism of CCAAT-Enhancer Binding Protein Recruitment by the TRIB1 Pseudokinase

Cited by 100 publications

References 64 publications

Structural Basis for Substrate Selectivity of the E3 Ligase COP1

Structural Basis for Substrate Selectivity of the E3 Ligase COP1

Structural basis of autoregulatory scaffolding by apoptosis signal-regulating kinase 1

The Tribble with APL: A New Road to Therapy

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