Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
Nat Commun. 2024 Nov 30;15(1):10425. doi: 10.1038/s41467-024-54889-5.
IRF2BP2 is a transcriptional coregulator that plays diverse regulatory roles in various cellular processes in either IRF2-dependent or IRF2-independent manner through interactions with protein partners via its RING domain; however, the underlying molecular mechanisms remain unclear. In this study, we conduct a motif discovery search on the sequences of interacting proteins IRF2 and VGLL4 of IRF2BP2 and identify a conserved RxSVI motif. Biochemical and structural data reveal that the RING domain binds to the motif-containing peptides of IRF2 and VGLL4 with comparable affinities and in a similar manner. The motif-containing peptides tend to form a short loop along with a short β-strand, which facilitates effective recognition and tight binding by the RING domain. Further exploration of this motif in the human proteome identifies the transcription factor ZBTB16 as an interacting protein of IRF2BP2. Biochemical, structural, and cell biological data demonstrate that the RING domain binds to the motif-containing peptide of ZBTB16 in a manner similar to that of IRF2 and VGLL4. Moreover, IRF2BP2 plays a crucial regulatory role in megakaryocytic differentiation through interaction with ZBTB16. These findings elucidate the molecular basis for how IRF2BP2 can engage with different protein partners, thereby exerting diverse regulatory functions in many cellular processes.
IRF2BP2 是一种转录共调节剂，通过其 RING 结构域与蛋白伴侣相互作用，以依赖或不依赖 IRF2 的方式在各种细胞过程中发挥多样化的调节作用；然而，其潜在的分子机制仍不清楚。在这项研究中，我们对 IRF2BP2 的相互作用蛋白 IRF2 和 VGLL4 的序列进行了基序发现搜索，并鉴定出一个保守的 RxSVI 基序。生化和结构数据显示，RING 结构域以相似的亲和力和方式结合 IRF2 和 VGLL4 的含基序肽。含基序的肽倾向于形成一个短环，以及一个短的 β-链，这有利于 RING 结构域的有效识别和紧密结合。进一步在人类蛋白质组中对该基序的探索确定转录因子 ZBTB16 是 IRF2BP2 的一个相互作用蛋白。生化、结构和细胞生物学数据表明，RING 结构域以类似于 IRF2 和 VGLL4 的方式结合 ZBTB16 的含基序肽。此外，IRF2BP2 通过与 ZBTB16 的相互作用在巨核细胞分化中发挥关键的调节作用。这些发现阐明了 IRF2BP2 如何与不同的蛋白伴侣结合，从而在许多细胞过程中发挥多样化的调节功能的分子基础。
