Homo-trimerization is essential for the transcription factor function of Myrf for oligodendrocyte differentiation.
Myrf is a key transcription factor for oligodendrocyte differentiation and central nervous system myelination. We and others have previously shown that Myrf is generated as a membrane protein in the endoplasmic reticulum (ER), and that it undergoes auto-processing to release its N-terminal fragment from the ER, which enters the nucleus to work as a transcription factor. These previous studies allow a glimpse into the unusual complexity behind the biogenesis and function of the transcription factor domain of Myrf. Here, we report that Myrf N-terminal fragments assemble into stable homo-trimers before ER release. Consequently, Myrf N-terminal fragments are released from the ER only as homo-trimers. Our re-analysis of a previous genetic screening result in Caenorhabditis elegans shows that homo-trimerization is essential for the biological functions of Myrf N-terminal fragment, and that the region adjacent to the DNA-binding domain is pivotal to its homo-trimerization. Further, our computational analysis uncovered a novel homo-trimeric DNA motif that mediates the homo-trimeric DNA binding of Myrf N-terminal fragments. Importantly, we found that homo-trimerization defines the DNA binding specificity of Myrf N-terminal fragments. In sum, our study elucidates the molecular mechanism governing the biogenesis and function of Myrf N-terminal fragments and its physiological significance.
Hunter James Kelly Research Institute, Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA.
Dongkyeong
D
Kim
Hunter James Kelly Research Institute, Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA.
Jin-Ok
JO
Choi
Hunter James Kelly Research Institute, Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA.
Chuandong
C
Fan
Hunter James Kelly Research Institute, Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA.
Randall S
RS
Shearer
Hunter James Kelly Research Institute, Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA.
Mohamed
M
Sharif
Hunter James Kelly Research Institute, Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA.
Patrick
P
Busch
Hunter James Kelly Research Institute, Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA.
Yungki
Y
Park
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D009836:Oligodendroglia / Q000166:cytology* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry; D011485:Protein Binding; D000072417:Protein Domains; D055503:Protein Multimerization; D051381:Rats; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic
D008565:Membrane Proteins; C409875:Myrf protein, human; D010446:Peptide Fragments; D014157:Transcription Factors; C571125:myelin gene regulatory factor, mouse; D004247:DNA