Elucidation of the gene expression mechanism by the heme -Bach2 pathway

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K08573
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Tohoku University
• Principal Investigator: MASTUI Miki 東北大学, 医学系研究科, JSPS特別研究員(RPD) (00455784)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: ヘム / 遺伝子発現

Outline of Final Research Achievements

Transcription factor Bach2 possess BTB and bZip domains, separated by long unstructured sequences. In addition, Bach2 protein contains a conserved Cys-Pro motif, which has been identified as the heme-binding site. Our previous studies of Bach2 revealed that when heme binding occurs in the intrinsically disordered region, the conformation of the region is altered. In this study, we identified the serine-threonine kinase, which directly bound to intrinsically disordered region of Bach2. This kinase inhibitor induced the cytoplasmic and nuclear localization of Bach2. Moreover, this kinase inhibitor acts on the repression activity of Bach2. The LC-MS/MS analysis of phosphorylated-site of Bach2 by this kinase in the presence or absence of heme showed that heme changed the phosphorylated-site of Bach2. These results suggested that heme regulates phosphorylated-site of intrinsically disordered region of Bach2 and releases of transcriptional repression activity of Bach2.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

本研究の特色は、研究対象であるBach2 が液性免疫における形質細胞分化、自然免疫におけるマクロファージの分化に重要な転写因子であり、かつBach2 が複数のヘムに制御される天然変性タンパク質であるという点にある。ヘムタンパク質の多くは安定な立体構造をとり、ヘムとタンパク質が1：1 で結合して機能しているものがほとんどである。これまでに、ヘムにより制御される天然変性タンパク質の報告はない。本研究によって、生体内でヘム濃度変化が液性免疫および自然免疫の重要なシグナル因子となる可能性が示された。