This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Histone lysine methyltransferase MLL1 complex is one of the most important complex in current epigenetics research. The catalytic core of this complex contains four components. MLL1, WDR5, RbBP5 and Ash2L. MLL1 is the catalytic component. However, by itself, MLL1 is not catalytically active. One in the presence of the other components, MLL1 can modify lysine 4 of histone H3. Recently, we determined the high resolution crystal structure of the WDR5-RbBP5-Ash2L complex. It shows a very flexible conformation. In the crystal structure, RbBP5 contacts with both WDR5 and Ash2L and WDR5 shows no direct interaction with Ash2L. Data from other labs showed that WDR5 directly binds to MLL1. In addition, from our biochemical studies, we also know that the addition of MLL1 to the WDR5-RbBP5-Ash2L subcomplex resulted in much higher enzymatic activity than MLL1 itself and this stimulation requires Ash2L and RbBP5 although neither of them could interact with MLL1 by themselves. We propose that the interaction between MLL1 and WDR5 in the WDR5-RbBP5-Ash2L complex recruits MLL1 to close vicinity to RbBP5 and Ash2L and this recruitment results in large range conformational change (from flexible complex with no enzymatic activity to a more compact structure with activity) that is suitable for detection by SAXS.
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