On 7 November 2022, an online paper titled ‘Structures of NPAS4-ARNT and NPAS4-ARNT2 heterodimers reveal new dimerization modalities in the bHLH-PAS transcription factor family’ was published in Proceedings of the National Academy of Sciences of the United States of America (PNAS). Xiangnan Sun, a PhD student of the group, was the first author of the paper, and Prof. Dalei Wu was the corresponding author, while Shandong University was the first and corresponding author’s affiliation.

Neuronal PAS domain protein 4 (NPAS4) is a transcription factor mainly distributed in the brain, belonging to the bHLH PAS (basic helix loop helix PER-ARNT-SIM) transcription factor family of nuclear receptors. It participates in regulating the expression of a series of downstream genes related to brain cognition and memory, and can maintain the excitatory inhibitory balance of neural circuits. In addition to nerve cells, NPAS4 is also present in pancreatic islets and vascular epithelial cells. NPAS4 dysfunction is related to depression, schizophrenia, autism and other neurodevelopmental disorders, so it is a potential new target for the treatment of these neuropsychiatric diseases. What’s more,it is expected to become a potential drug target related to type II diabetes, pancreas transplantation and angiogenesis.

This study was the first to resolve the structure of NPAS4 in complex with two dimerisation partner proteins and DNA, visualising the unique structure of the NPAS4 subunit and showing the different dimerisation modes of NPAS4-ARNT and NPAS4-ARNT2. It revealed that ARNT binds to NPAS4 differently than it binds to other members of the bHLH-PAS family, expanding our understanding of the heterodimerisation patterns of this family. In view of the close relationship between NPAS4 and human diseases, the structural analysis of NPAS4 lays a foundation for the discovery of drugs targeting NPAS4 in the future.

This work was supported by grants from Shandong Provincial Natural Science Foundation, National Natural Science Foundation of China, Interdisciplinary Innovative Research Group Program of Shandong University, and Taishan Scholars Project of Shandong. It was provided important support for this work by Core Facilities for Life and Environmental Sciences of Shandong University, National Facility for Protein Science in Shanghai and Shanghai Synchrotron Radiation Facility.

Full text link: https://www.pnas.org/doi/10.1073/pnas.2208804119

Figure source & Editor: Xiangnan Sun