biostudies-literatureSun XTaishan Scholar Project of Shandong ProvinceNational Natural Science Foundation of ChinaShandong UniversityWellcome Trust山东省科学技术厅 | Natural Science Fund for Distinguished Young Scholars of Shandong ProvinceNatural Science Foundation of Jiangsu Provincee2208804119https://www.ebi.ac.uk/biostudies/studies/S-EPMC9674253biostudies-literatureUnknown119(46)Neuronal PER-ARNT-SIM (PAS) domain protein 4 (NPAS4) is a protective transcriptional regulator whose dysfunction has been linked to a variety of neuropsychiatric and metabolic diseases. As a member of the basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) transcription factor family, NPAS4 is distinguished by an ability to form functional heterodimers with aryl hydrocarbon receptor nuclear translocator (ARNT) and ARNT2, both of which are also bHLH-PAS family members. Here, we describe the quaternary architectures of NPAS4-ARNT and NPAS4-ARNT2 heterodimers in complexes involving DNA response elements. Our crystallographic studies reveal a uniquely interconnected domain conformation for the NPAS4 protein itself, as well as its differentially configured heterodimeric arrangements with both ARNT aProceedings of the National Academy of Sciences of the United States of AmericaStructures of NPAS4-ARNT and NPAS4-ARNT2 heterodimers reveal new dimerization modalities in the bHLH-PAS transcription factor family.PMC9674253tsqn201909004ZR2021JQ302020QNQT009210664/Z/18/ZBK2017039922177063Jing LDiao XLi FRastinejad FZhang MWu DSun XZhuang JfalseStructures of NPAS4-ARNT and NPAS4-ARNT2 heterodimers reveal new dimerization modalities in the bHLH-PAS transcription factor family.Neuronal PER-ARNT-SIM (PAS) domain protein 4 (NPAS4) is a protective transcriptional regulator whose dysfunction has been linked to a variety of neuropsychiatric and metabolic diseases. As a member of the basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) transcription factor family, NPAS4 is distinguished by an ability to form functional heterodimers with aryl hydrocarbon receptor nuclear translocator (ARNT) and ARNT2, both of which are also bHLH-PAS family members. Here, we describe the quaternary architectures of NPAS4-ARNT and NPAS4-ARNT2 heterodimers in complexes involving DNA response elements. Our crystallographic studies reveal a uniquely interconnected domain conformation for the NPAS4 protein itself, as well as its differentially configured heterodimeric arrangements with both ARNT a2022-01-01T00:00:00Z2022 Nov2026-05-10T06:50:57.388Z2025-02-19T03:25:51.83ZS-EPMC96742533634325310.1073/pnas.2208804119