an ash2lrbbp5 heterodimer stimulates the mll1 methyltransferase activity through coordinated substrate interactions with the mll1 set domain通过协调一个ash2lrbbp5异质二聚体刺激mll1甲基转移酶活性衬底与mll1集域的交互.pdfVIP

An Ash2L/RbBP5 Heterodimer Stimulates the MLL1 Methyltransferase Activity through Coordinated Substrate Interactions with the MLL1 SET Domain 1. 2. 1 1 1 2,3 1,2 Fang Cao , Yong Chen , Tomasz Cierpicki , Yifan Liu , Venkatesha Basrur , Ming Lei *, Yali Dou * 1 Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States of America, 2 Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan, United States of America, 3 Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan, United States of America Abstract Histone H3 lysine 4 (K4) methylation is a prevalent mark associated with transcription activation and is mainly catalyzed by the MLL/SET1 family histone methyltransferases. A common feature of the mammalian MLL/SET1 complexes is the presence of three core components (RbBP5, Ash2L and WDR5) and a catalytic subunit containing a SET domain. Unlike most other histone lysine methyltransferases, all four proteins are required for efficient H3 K4 methylation. Despite extensive efforts, mechanisms for how three core components regulate MLL/SET1 methyltransferase activity remain elusive. Here we show that a heterodimer of Ash2L and RbBP5 has intrinsic histone methyltransferase activity. This activity requires the highly conserved SPRY domain of Ash2L and a short peptide of RbBP5. We demonstrate that both Ash2L and the MLL1 SET domain are capable of binding to S-adenosyl-L- [methyl-3H] methionine in the MLL1 core complex. Mutations in the MLL1 SET domain that fail to support overall H3 K4 methylation also compromise SAM binding by Ash2L. Taken together, our results show that the Ash2L/RbBP5 heterodimer p