Structural and functional analysis of the DOT1L–AF10 complex reveals mechanistic insights into MLL-AF10-associated leukemogenesis
| Autor: | Heng Zhang, Su Qin, Rachel Harding, Vinod Nayak, Wolfram Tempel, Peter Loppnau, Bo Zhou, Yali Dou, Yanjun Li, Jing Xu, Jinrong Min |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular 0301 basic medicine Leucine zipper Protein domain Biology DNA-binding protein Structure-Activity Relationship Research Communication 03 medical and health sciences 0302 clinical medicine Protein Domains hemic and lymphatic diseases Gene cluster Genetics Humans Protein Structure Quaternary neoplasms Transcription factor Homeodomain Proteins Histone-Lysine N-Methyltransferase Methyltransferases DOT1L Cell biology Gene Expression Regulation Neoplastic Zinc Cell Transformation Neoplastic 030104 developmental biology 030220 oncology & carcinogenesis Homeobox Myeloid-Lymphoid Leukemia Protein Crystallization Protein Binding Transcription Factors Developmental Biology |
| Zdroj: | Genes & Development. 32:341-346 |
| ISSN: | 1549-5477 0890-9369 |
| Popis: | The mixed-lineage leukemia (MLL)-AF10 fusion oncoprotein recruits DOT1L to the homeobox A (HOXA) gene cluster through its octapeptide motif leucine zipper (OM-LZ), thereby inducing and maintaining the MLL-AF10-associated leukemogenesis. However, the recognition mechanism between DOT1L and MLL-AF10 is unclear. Here, we present the crystal structures of both apo AF10OM-LZ and its complex with the coiled-coil domain of DOT1L. Disruption of the DOT1L–AF10 interface abrogates MLL-AF10-associated leukemic transformation. We further show that zinc stabilizes the DOT1L–AF10 complex and may be involved in the regulation of the HOXA gene expression. Our studies may also pave the way for the rational design of therapeutic drugs against MLL-rearranged leukemia. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|