NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors

Wu, Dalei; Su, Xiaoyu; Potluri, Nalini; Kim, Youngchang; Rastinejad, Fraydoon

doi:10.7554/eLife.18790

Title: NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors

Journal Article · Wed Oct 26 00:00:00 EDT 2016 · eLife

DOI:https://doi.org/10.7554/eLife.18790· OSTI ID:1347613

Wu, Dalei ^[1]; Su, Xiaoyu ^[2]; Potluri, Nalini ^[2]; Kim, Youngchang ^[3];

^[2]

Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL (United States); Shandong Univ., Qingdao (China)
Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL (United States)
Argonne National Lab. (ANL), Argonne, IL (United States)

Here, the neuronal PAS domain proteins NPAS1 and NPAS3 are members of the basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) family, and their genetic deficiencies are linked to a variety of human psychiatric disorders including schizophrenia, autism spectrum disorders and bipolar disease. NPAS1 and NPAS3 must each heterodimerize with the aryl hydrocarbon receptor nuclear translocator (ARNT), to form functional transcription complexes capable of DNA binding and gene regulation. Here we examined the crystal structures of multi-domain NPAS1-ARNT and NPAS3-ARNT-DNA complexes, discovering each to contain four putative ligand-binding pockets. Through expanded architectural comparisons between these complexes and HIF-1α-ARNT, HIF-2α-ARNT and CLOCK-BMAL1, we show the wider mammalian bHLH-PAS family is capable of multi-ligand-binding and presents as an ideal class of transcription factors for direct targeting by small-molecule drugs.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Institutes of Health (NIH); US Army Research Office (ARO); USDOE

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1347613

Journal Information:: eLife, Vol. 5; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 38 works

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References (49)

PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Involvement of estrogen-related receptors in transcriptional response to hypoxia and growth of solid tumors Ao, A.; Wang, H.; Kamarajugadda, S. Proceedings of the National Academy of Sciences, Vol. 105, Issue 22 https://doi.org/10.1073/pnas.0711677105	journal	May 2008
Human Variants in the Neuronal Basic Helix-Loop-Helix/Per-Arnt-Sim (bHLH/PAS) Transcription Factor Complex NPAS4/ARNT2 Disrupt Function Bersten, David C.; Bruning, John B.; Peet, Daniel J. PLoS ONE, Vol. 9, Issue 1 https://doi.org/10.1371/journal.pone.0085768	journal	January 2014
bHLH–PAS proteins in cancer Bersten, David C.; Sullivan, Adrienne E.; Peet, Daniel J. Nature Reviews Cancer, Vol. 13, Issue 12 https://doi.org/10.1038/nrc3621	journal	November 2013
SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information Biasini, Marco; Bienert, Stefan; Waterhouse, Andrew Nucleic Acids Research, Vol. 42, Issue W1 https://doi.org/10.1093/nar/gku340	journal	April 2014
Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi–like features Bonnefond, Amélie; Raimondo, Anne; Stutzmann, Fanny Journal of Clinical Investigation, Vol. 123, Issue 7 https://doi.org/10.1172/JCI68035	journal	June 2013
Abnormal neurodevelopment, neurosignaling and behaviour in Npas3-deficient mice: Npas3-deficient mice Brunskill, Eric W.; Ehrman, Lisa A.; Williams, Michael T. European Journal of Neuroscience, Vol. 22, Issue 6 https://doi.org/10.1111/j.1460-9568.2005.04291.x	journal	September 2005
Characterization of Npas3 , a novel basic helix-loop-helix PAS gene expressed in the developing mouse nervous system Brunskill, Eric W.; Witte, David P.; Shreiner, Andrew B. Mechanisms of Development, Vol. 88, Issue 2 https://doi.org/10.1016/S0925-4773(99)00182-3	journal	November 1999
MolProbity : all-atom structure validation for macromolecular crystallography Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/S0907444909042073	journal	December 2009
Exactly the Same but Different: Promiscuity and Diversity in the Molecular Mechanisms of Action of the Aryl Hydrocarbon (Dioxin) Receptor Denison, Michael S.; Soshilov, Anatoly A.; He, Guochun Toxicological Sciences, Vol. 124, Issue 1 https://doi.org/10.1093/toxsci/kfr218	journal	September 2011
NPAS2: A Gas-Responsive Transcription Factor Dioum, E. M. Science, Vol. 298, Issue 5602 https://doi.org/10.1126/science.1078456	journal	November 2002
Altered Patterns of Sleep and Behavioral Adaptability in NPAS2-Deficient Mice Dudley, C. A. Science, Vol. 301, Issue 5631 https://doi.org/10.1126/science.1082795	journal	July 2003
CASTp: computed atlas of surface topography of proteins with structural and topographical mapping of functionally annotated residues Dundas, J.; Ouyang, Z.; Tseng, J. Nucleic Acids Research, Vol. 34, Issue Web Server https://doi.org/10.1093/nar/gkl282	journal	July 2006
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
Behavioral and regulatory abnormalities in mice deficient in the NPAS1 and NPAS3 transcription factors Erbel-Sieler, C.; Dudley, C.; Zhou, Y. Proceedings of the National Academy of Sciences, Vol. 101, Issue 37 https://doi.org/10.1073/pnas.0405310101	journal	September 2004
Unsaturated fatty acids as high-affinity ligands of the C-terminal Per-ARNT-Sim domain from the Hypoxia-inducible factor 3α Fala, Angela M.; Oliveira, Juliana F.; Adamoski, Douglas Scientific Reports, Vol. 5, Issue 1 https://doi.org/10.1038/srep12698	journal	August 2015
Circadian clock control of endocrine factors Gamble, Karen L.; Berry, Ryan; Frank, Stuart J. Nature Reviews Endocrinology, Vol. 10, Issue 8 https://doi.org/10.1038/nrendo.2014.78	journal	May 2014
cDNA cloning and tissue-specific expression of a novel basic helix-loop-helix/PAS factor (Arnt2) with close sequence similarity to the aryl hydrocarbon receptor nuclear translocator (Arnt). Hirose, K.; Morita, M.; Ema, M. Molecular and Cellular Biology, Vol. 16, Issue 4 https://doi.org/10.1128/MCB.16.4.1706	journal	April 1996
Cross-Disorder Genomewide Analysis of Schizophrenia, Bipolar Disorder, and Depression Huang, Jie; Perlis, Roy H.; Lee, Phil H. American Journal of Psychiatry, Vol. 167, Issue 10 https://doi.org/10.1176/appi.ajp.2010.09091335	journal	October 2010
Crystal Structure of the Heterodimeric CLOCK:BMAL1 Transcriptional Activator Complex Huang, N.; Chelliah, Y.; Shan, Y. Science, Vol. 337, Issue 6091 https://doi.org/10.1126/science.1222804	journal	May 2012
Structural Overview of the Nuclear Receptor Superfamily: Insights into Physiology and Therapeutics Huang, Pengxiang; Chandra, Vikas; Rastinejad, Fraydoon Annual Review of Physiology, Vol. 72, Issue 1 https://doi.org/10.1146/annurev-physiol-021909-135917	journal	March 2010
Disruption of the neuronal PAS3 gene in a family affected with schizophrenia Kamnasaran, D. Journal of Medical Genetics, Vol. 40, Issue 5 https://doi.org/10.1136/jmg.40.5.325	journal	May 2003
Targeted mutation of the murine arylhydrocarbon receptor nuclear translocator 2 (Arnt2) gene reveals partial redundancy with Arnt Keith, B.; Adelman, D. M.; Simon, M. C. Proceedings of the National Academy of Sciences, Vol. 98, Issue 12 https://doi.org/10.1073/pnas.121494298	journal	May 2001
The 'AHR diet' for mucosal homeostasis Leavy, Olive Nature Reviews Immunology, Vol. 11, Issue 12 https://doi.org/10.1038/nri3115	journal	November 2011
Anatomy of protein pockets and cavities: Measurement of binding site geometry and implications for ligand design Liang, Jie; Woodward, Clare; Edelsbrunner, Herbert Protein Science, Vol. 7, Issue 9 https://doi.org/10.1002/pro.5560070905	journal	September 1998
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Mammalian Per-Arnt-Sim Proteins in Environmental Adaptation McIntosh, Brian E.; Hogenesch, John B.; Bradfield, Christopher A. Annual Review of Physiology, Vol. 72, Issue 1 https://doi.org/10.1146/annurev-physiol-021909-135922	journal	March 2010
ARNT2 acts as the dimerization partner of SIM1 for the development of the hypothalamus Michaud, Jacques L.; DeRossi, Charles; May, Noah R. Mechanisms of Development, Vol. 90, Issue 2 https://doi.org/10.1016/S0925-4773(99)00328-7	journal	February 2000
Novel function of neuronal PAS domain protein 1 in erythropoietin expression in neuronal cells Ohsawa, Shizue; Hamada, Shun; Kakinuma, Yoshihiko Journal of Neuroscience Research, Vol. 79, Issue 4 https://doi.org/10.1002/jnr.20365	journal	February 2005
Identification of a Novel Basic Helix-Loop-Helix-PAS Factor, NXF, Reveals a Sim2 Competitive, Positive Regulatory Role in Dendritic-Cytoskeleton Modulator Drebrin Gene Expression Ooe, Norihisa; Saito, Koichi; Mikami, Nobuyoshi Molecular and Cellular Biology, Vol. 24, Issue 2 https://doi.org/10.1128/MCB.24.2.608-616.2004	journal	January 2004
Structural and Functional Characterization of the Aryl Hydrocarbon Receptor Ligand Binding Domain by Homology Modeling and Mutational Analysis ^† Pandini, Alessandro; Denison, Michael S.; Song, Yujuan Biochemistry, Vol. 46, Issue 3 https://doi.org/10.1021/bi061460t	journal	January 2007
Three circadian clock genes Per2, Arntl, and Npas2 contribute to winter depression Partonen, Timo; Treutlein, Jens; Alpman, Asude Annals of Medicine, Vol. 39, Issue 3 https://doi.org/10.1080/07853890701278795	journal	January 2007
Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder Pickard, B. S.; Christoforou, A.; Thomson, P. A. Molecular Psychiatry, Vol. 14, Issue 9 https://doi.org/10.1038/mp.2008.24	journal	March 2008
The neuronal PAS domain protein 3 transcription factor controls FGF-mediated adult hippocampal neurogenesis in mice Pieper, A. A.; Wu, X.; Han, T. W. Proceedings of the National Academy of Sciences, Vol. 102, Issue 39 https://doi.org/10.1073/pnas.0506713102	journal	September 2005
Npas4 Regulates a Transcriptional Program in CA3 Required for Contextual Memory Formation Ramamoorthi, K.; Fropf, R.; Belfort, G. M. Science, Vol. 334, Issue 6063 https://doi.org/10.1126/science.1208049	journal	December 2011
NPAS2: An Analog of Clock Operative in the Mammalian Forebrain Reick, M. Science, Vol. 293, Issue 5529 https://doi.org/10.1126/science.1060699	journal	July 2001
Identification of the Ah Receptor Nuclear Translocator Protein (Arnt) as a Component of the DNA Binding Form of the Ah Receptor Reyes, H.; Reisz-Porszasz, S.; Hankinson, O. Science, Vol. 256, Issue 5060 https://doi.org/10.1126/science.256.5060.1193	journal	May 1992
Allosteric inhibition of hypoxia inducible factor-2 with small molecules Scheuermann, Thomas H.; Li, Qiming; Ma, He-Wen Nature Chemical Biology, Vol. 9, Issue 4 https://doi.org/10.1038/nchembio.1185	journal	February 2013
Hypoxia-Inducible Factors in Physiology and Medicine Semenza, Gregg L. Cell, Vol. 148, Issue 3, p. 399-408 https://doi.org/10.1016/j.cell.2012.01.021	journal	February 2012
Ligand Displaces Heat Shock Protein 90 from Overlapping Binding Sites within the Aryl Hydrocarbon Receptor Ligand-binding Domain Soshilov, Anatoly; Denison, Michael S. Journal of Biological Chemistry, Vol. 286, Issue 40 https://doi.org/10.1074/jbc.M111.246439	journal	August 2011
NPAS1 Represses the Generation of Specific Subtypes of Cortical Interneurons Stanco, Amelia; Pla, Ramón; Vogt, Daniel Neuron, Vol. 84, Issue 5 https://doi.org/10.1016/j.neuron.2014.10.040	journal	December 2014
Endogenous and Exogenous Ligands of Aryl Hydrocarbon Receptor: Current State of Art Stejskalova, Lucie; Dvorak, Zdenek; Pavek, Petr Current Drug Metabolism, Vol. 12, Issue 2 https://doi.org/10.2174/138920011795016818	journal	February 2011
T cells hang in the balance Stevens, Emily A.; Bradfield, Christopher A. Nature, Vol. 453, Issue 7191 https://doi.org/10.1038/453046a	journal	April 2008
Neuronal PAS Domain Protein 1 Is a Transcriptional Repressor and Requires Arylhydrocarbon Nuclear Translocator for Its Nuclear Localization Teh, Christina H. L.; Lam, Kevin K. Y.; Loh, Chin C. Journal of Biological Chemistry, Vol. 281, Issue 45 https://doi.org/10.1074/jbc.M604409200	journal	September 2006
Neuronal PAS domain protein 1 regulates tyrosine hydroxylase level in dopaminergic neurons Teh, Christina H. L.; Loh, Chin Chieh; Lam, Kevin K. Y. Journal of Neuroscience Research, Vol. 85, Issue 8 https://doi.org/10.1002/jnr.21312	journal	June 2007
Role of basic region leucine zipper transcription factors cyclic AMP response element binding protein (CREB), CREB2, activating transcription factor 2 and CAAT/enhancer binding protein alpha in cyclic AMP response element-mediated transcription Thiel, Gerald; Al Sarraj, Jude; Vinson, Charles Journal of Neurochemistry, Vol. 92, Issue 2 https://doi.org/10.1111/j.1471-4159.2004.02882.x	journal	January 2005
Structure and Dimerization Properties of the Aryl Hydrocarbon Receptor PAS-A Domain Wu, D.; Potluri, N.; Kim, Y. Molecular and Cellular Biology, Vol. 33, Issue 21 https://doi.org/10.1128/MCB.00698-13	journal	September 2013
Structural integration in hypoxia-inducible factors Wu, Dalei; Potluri, Nalini; Lu, Jingping Nature, Vol. 524, Issue 7565 https://doi.org/10.1038/nature14883	journal	August 2015
Molecular characterization of two mammalian bHLH-PAS domain proteins selectively expressed in the central nervous system Zhou, Y. -D.; Barnard, M.; Tian, H. Proceedings of the National Academy of Sciences, Vol. 94, Issue 2 https://doi.org/10.1073/pnas.94.2.713	journal	January 1997

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