Self-assembly of the bZIP transcription factor ΔFosB

Yin, Zhou; Venkannagari, Harikanth; Lynch, Haley; Aglyamova, Galina V.; Bhandari, Mukund; Machius, Mischa; Nestler, Eric J.; Robison, Alfred J.; Rudenko, Gabby

doi:10.1016/j.crstbi.2019.12.001

Cited by 6 publications

(4 citation statements)

References 51 publications

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“…Although most data point to other FOS family proteins requiring a JUN family partner to form a function AP1 complex, ΔFOSB uniquely can form homodimers that bind AP1 consensus sequences in vitro . Further, the bZIP domain of ΔFOSB can even form tetrameric structures that defy canonical AP1 arrangements (Figure A), and we have provided some evidence that ΔFOSB is found in complexes consistent with tetramers in cultured cells . These observations suggest that, once a chronic stimulus causes induction of the ΔFOSB protein exceeding a threshold within a cell, perhaps swamping ambient concentrations of JUND, its major binding partner in vivo , self-assembly occurs generating several noncanonical molecular arrangements whose function and potential gene targets have yet to be determined.…”

Section: δFosb Structure and Functionmentioning

confidence: 69%

“…108 Further, the bZIP domain of ΔFOSB can even form tetrameric structures that defy canonical AP1 arrangements (Figure 2A), and we have provided some evidence that ΔFOSB is found in complexes consistent with tetramers in cultured cells. 109 These observations suggest that, once a chronic stimulus causes induction of the ΔFOSB protein exceeding a threshold within a cell, perhaps swamping ambient concentrations of JUND, its major binding partner in vivo, 110 self-assembly occurs generating several noncanonical molecular arrangements whose function and potential gene targets have yet to be determined. Moreover, ΔFOSB complexes may be stabilized by oxidation, as recent in vitro (cell-free and cell-based) experiments suggest that ΔFOSB cysteine 172 (C172) can form a disulfide bond with C279 of JUND in the canonical heterodimeric AP1 complex and that ΔFOSB C172 may form a disulfide bond with C172 of a partner ΔFOSB in a noncanonical homodimeric complex.…”

Section: ■ δFosb Structure and Functionmentioning

confidence: 99%

“…Moreover, ΔFOSB complexes may be stabilized by oxidation, as recent in vitro (cell-free and cell-based) experiments suggest that ΔFOSB cysteine 172 (C172) can form a disulfide bond with C279 of JUND in the canonical heterodimeric AP1 complex and that ΔFOSB C172 may form a disulfide bond with C172 of a partner ΔFOSB in a noncanonical homodimeric complex. 109,111 These properties, some unique to ΔFOSB and others shared by FOS/JUN family members, have made ΔFOSB an intriguing target of study in fields ranging from neuropsychiatric disease to oncology for decades. However, to fully elucidate the role of ΔFOSB in physiology and disease and to potentially exploit it as a target for therapeutic intervention, many outstanding questions remain to be addressed.…”

Section: ■ δFosb Structure and Functionmentioning

confidence: 99%

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ΔFOSB: A Potentially Druggable Master Orchestrator of Activity-Dependent Gene Expression

Robison

Nestler

2022

ACS Chem. Neurosci.

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ΔFOSB is a uniquely stable member of the FOS family of immediate early gene AP1 transcription factors. Its accumulation in specific cell types and tissues in response to a range of chronic stimuli is associated with biological phenomena as diverse as memory formation, drug addiction, stress resilience, and immune cell activity. Causal connections between ΔFOSB expression and the physiological and behavioral sequelae of chronic stimuli have been established in rodent and, in some cases, primate models for numerous healthy and pathological states with such preclinical observations often supported by human data demonstrating tissue-specific ΔFOSB expression associated with several specific syndromes. However, the viability of ΔFOSB as a target for therapeutic intervention might be questioned over presumptive concerns of side effects given its expression in such a wide range of cell types and circumstances. Here, we summarize numerous insights from the past three decades of research into ΔFOSB structure, function, mechanisms of induction, and regulation of target genes that support its potential as a druggable target. We pay particular attention to the potential for targeting distinct ΔFOSB isoforms or distinct ΔFOSB-containing multiprotein complexes to achieve cell type or tissue specificity to overcome off-target concerns. We also cover critical gaps in knowledge that currently limit the exploitation of ΔFOSB’s therapeutic possibilities and how they may be addressed. Finally, we summarize both current and potential future strategies for generating small molecules or genetic tools for the manipulation of ΔFOSB in the clinic.

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Section: δFosb Structure and Functionmentioning

confidence: 69%

Section: ■ δFosb Structure and Functionmentioning

confidence: 99%

Section: ■ δFosb Structure and Functionmentioning

confidence: 99%

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ΔFOSB: A Potentially Druggable Master Orchestrator of Activity-Dependent Gene Expression

Robison

Nestler

2022

ACS Chem. Neurosci.

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“…The BR mediates DNA recognition and is enriched in positively charged amino acids (43). As shown in a number of X-ray structures, a bZIP assumes a chopstick-like structure of two uninterrupted α-helices grasping the DNA by the major groove (44)(45)(46)(47)(48)(49)(50)(51). Although the bZIP domains have been studied for more than 30 years, there are few details on the mechanism of their binding to DNA.…”

Section: Introductionmentioning

confidence: 99%

The transition state for coupled folding and binding of a disordered DNA binding domain resembles the unbound state

Kuravsky,

Kelly,

Redfield

et al. 2024

Preprint

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The basic zippers (bZIPs) are one of two large eukaryotic families of transcription factors whose DNA binding domains are disordered in isolation but fold into stable α-helices upon target DNA binding. Here we systematically disrupt pre-existing helical propensity within the DNA binding region of the homodimeric bZIP domain of cAMP-response element binding protein (CREB) using Ala-Gly scanning and examine the impact on target binding kinetics. We find that the secondary structure of the transition state strongly resembles that of the unbound state. The closest residue to the dimerisation domain that has been examined is largely folded within both unbound and transition states; dimerisation apparently propagates additional helical propensity into the basic region. The results are consistent with electrostatically-enhanced DNA binding, followed by rapid folding from the folded zipper outwards. Interestingly, despite taking the exact experimental approach suggested for testing it, we find no evidence for disorder-mediated rate enhancement predicted by fly-casting theory.

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Exploring the potential link between ΔFosB and N-acetylcysteine in craving/relapse dynamics: can N-acetylcysteine stand out as a possible treatment candidate?

Arjmand,

Ilaghi,

Shafie’ei

et al. 2024

Acta Neuropsychiatr.

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From a neuroscientific point of view, one of the unique archetypes of substance use disorders is its road to relapse, in which the reward system plays a crucial role. Studies on the neurobiology of substance use disorders have highlighted the central role of a protein belonging to the Fos family of transcription factors, ΔFosB. Relying on the roles ΔFosB plays in the pathophysiology of substance use disorders, we endeavour to present some evidence demonstrating that N-acetylcysteine, a low-cost and well-tolerated over-the-counter medicine, may influence the downstream pathway of ΔFosB, thereby serving as a treatment strategy to mitigate the risk of relapse in cases of substance use.

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Self-assembly of the bZIP transcription factor ΔFosB

Cited by 6 publications

References 51 publications

ΔFOSB: A Potentially Druggable Master Orchestrator of Activity-Dependent Gene Expression

ΔFOSB: A Potentially Druggable Master Orchestrator of Activity-Dependent Gene Expression

The transition state for coupled folding and binding of a disordered DNA binding domain resembles the unbound state

Exploring the potential link between ΔFosB and N-acetylcysteine in craving/relapse dynamics: can N-acetylcysteine stand out as a possible treatment candidate?

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