bHLH-PAS proteins: Functional specification through modular domain architecture

Michael, AK; Cl, Partch

doi:10.13172/2052-9651-1-2-1123

Cited by 10 publications

(10 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Functional studies augment the crystal structure models and demonstrate that intrinsically disordered regions in both CLOCK and BMAL1 (Figure 8 A) play critical roles in regulation of CLOCK:BMAL1 activity in vivo , 2 , 52 − 54 , 133 , 134 as they do within the larger bHLH-PAS family of transcription factors. 135 …”

Section: Clock:bmal1: the Principal Circadian Transcription Factormentioning

confidence: 99%

Emerging Models for the Molecular Basis of Mammalian Circadian Timing

Gustafson

Partch

2014

Biochemistry

View full text Add to dashboard Cite

Mammalian circadian timekeeping arises from a transcription-based feedback loop driven by a set of dedicated clock proteins. At its core, the heterodimeric transcription factor CLOCK:BMAL1 activates expression of Period, Cryptochrome, and Rev-Erb genes, which feed back to repress transcription and create oscillations in gene expression that confer circadian timing cues to cellular processes. The formation of different clock protein complexes throughout this transcriptional cycle helps to establish the intrinsic ∼24 h periodicity of the clock; however, current models of circadian timekeeping lack the explanatory power to fully describe this process. Recent studies confirm the presence of at least three distinct regulatory complexes: a transcriptionally active state comprising the CLOCK:BMAL1 heterodimer with its coactivator CBP/p300, an early repressive state containing PER:CRY complexes, and a late repressive state marked by a poised but inactive, DNA-bound CLOCK:BMAL1:CRY1 complex. In this review, we analyze high-resolution structures of core circadian transcriptional regulators and integrate biochemical data to suggest how remodeling of clock protein complexes may be achieved throughout the 24 h cycle. Defining these detailed mechanisms will provide a foundation for understanding the molecular basis of circadian timing and help to establish new platforms for the discovery of therapeutics to manipulate the clock.

show abstract

Section: Clock:bmal1: the Principal Circadian Transcription Factormentioning

confidence: 99%

Emerging Models for the Molecular Basis of Mammalian Circadian Timing

Gustafson

Partch

2014

Biochemistry

View full text Add to dashboard Cite

show abstract

“…Neuronal Per-Arnt-Sim domain–containing protein 4 (NPAS4) 2 (also known as neuronal transcription factor (NXF), limbic-enriched PAS domain protein (LE-PAS), and PAS domain–containing protein 10 (PASD10)) belongs to the basic helix–loop–helix (bHLH)-Per-Arnt-Sim (PAS) family of transcription factors ( 1 , 2 ). This family of proteins is well-conserved from metazoans to humans and plays important roles in maintaining cellular health by acting as environmental sensors ( 3 ). The bHLH-PAS family is divided into two classes according to the mechanism of dimerization.…”

Section: Introductionmentioning

confidence: 99%

Multiple sequences orchestrate subcellular trafficking of neuronal PAS domain–containing protein 4 (NPAS4)

Greb‐Markiewicz

Zarębski

Ożyhar

2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

Neuronal Per-Arnt-Sim (PAS) domain–containing protein 4 (NPAS4) is a basic helix–loop–helix (bHLH)-PAS transcription factor first discovered in neurons in the neuronal layer of the mammalian hippocampus and later discovered in pancreatic β-cells. NPAS4 has been proposed as a therapeutic target not only for depression and neurodegenerative diseases associated with synaptic dysfunction but also for type 2 diabetes and pancreas transplantation. The ability of bHLH-PAS proteins to fulfil their function depends on their intracellular trafficking, which is regulated by specific sequences, i.e. the nuclear localization signal (NLS) and the nuclear export signal (NES). However, until now, no study examining the subcellular localization signals of NPAS4 has been published. We show here that Rattus norvegicus NPAS4 was not uniformly localized in the nuclei of COS-7 and N2a cells 24 h after transfection. Additionally, cytoplasmic localization of NPAS4 was leptomycin B-sensitive. We demonstrate that NPAS4 possesses a unique arrangement of localization signals. Its bHLH domain contains an overlapping NLS and NES. We observed that its PAS-2 domain contains an NLS, an NES, and a second, proximally located, putative NLS. Moreover, the C terminus of NPAS4 contains two active NESs that overlap with a putative NLS. Our data indicate that glucose concentration could be one of the factors influencing NPAS4 localization. The presence of multiple localization signals and the differentiated localization of NPAS4 suggest a precise, multifactor-dependent regulation of NPAS4 trafficking, potentially crucial for its ability to act as a cellular stress sensor and transcription factor.

show abstract

“…Met and Gce belong to a family of basic helix-loop-helix/Per-Arnt-Sim (bHLH-PAS) transcription factors [ 9 , 10 ]. bHLH-PAS family members are responsible for the regulation of important developmental and physiological processes [ 11 , 12 ] and present a relatively well-conserved domain structure [ 13 ]. bHLH domains are typically responsible for DNA binding and dimerization, whereas PAS domains are crucial for selecting dimerization partner and ensuring the specificity of target gene activation [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…Such regulation takes place in the mammalian proteins SIM1 (single minded 1) and SIM2 (single minded 2), both of which are bHLH-PAS transcription factors that regulate the expression of genes in midline cells during development. SIM1 and SIM2 exhibit highly homologous PAS domains (90% of sequence similarity), but they are highly divergent at their C-termini [ 13 ]. Both proteins have been shown to heterodimerize with ARNT (aryl hydrocarbon nuclear translocator).…”

Section: Introductionmentioning

confidence: 99%

Intrinsic Disorder of the C-Terminal Domain of Drosophila Methoprene-Tolerant Protein

et al. 2016

View full text Add to dashboard Cite

Methoprene tolerant protein (Met) has recently been confirmed as the long-sought juvenile hormone (JH) receptor. This protein plays a significant role in the cross-talk of the 20-hydroxyecdysone (20E) and JH signalling pathways, which are important for control of insect development and maturation. Met belongs to the basic helix-loop-helix/Per-Arnt-Sim (bHLH-PAS) family of transcription factors. In these proteins, bHLH domains are typically responsible for DNA binding and dimerization, whereas the PAS domains are crucial for the choice of dimerization partner and the specificity of target gene activation. The C-terminal region is usually responsible for the regulation of protein complex activity. The sequence of the Met C-terminal region (MetC) is not homologous to any sequence deposited in the Protein Data Bank (PDB) and has not been structurally characterized to date. In this study, we show that the MetC exhibits properties typical for an intrinsically disordered protein (IDP). The final averaged structure obtained with small angle X-ray scattering (SAXS) experiments indicates that intrinsically disordered MetC exists in an extended conformation. This extended shape and the long unfolded regions characterise proteins with high flexibility and dynamics. Therefore, we suggest that the multiplicity of conformations adopted by the disordered MetC is crucial for its activity as a biological switch modulating the cross-talk of different signalling pathways in insects.

show abstract

bHLH-PAS proteins: Functional specification through modular domain architecture

Cited by 10 publications

References 41 publications

Emerging Models for the Molecular Basis of Mammalian Circadian Timing

Emerging Models for the Molecular Basis of Mammalian Circadian Timing

Multiple sequences orchestrate subcellular trafficking of neuronal PAS domain–containing protein 4 (NPAS4)

Intrinsic Disorder of the C-Terminal Domain of Drosophila Methoprene-Tolerant Protein

Contact Info

Product

Resources

About