Two Loops Undergoing Concerted Dynamics Regulate the Activity of the ASH1L Histone Methyltransferase.

ABSTRACT: ASH1L (absent, small, or homeotic-like 1) is a histone methyltransferase (HMTase) involved in gene activation that is overexpressed in multiple forms of cancer. Previous studies of ASH1L's catalytic SET domain identified an autoinhibitory loop that blocks access of histone substrate to the enzyme active site. Here, we used both nuclear magnetic resonance and X-ray crystallography to identify conformational dynamics in the ASH1L autoinhibitory loop. Using site-directed mutagenesis, we found that point mutations in the autoinhibitory loop that perturb the structure of the SET domain result in decreased enzyme activity, indicating that the autoinhibitory loop is not a simple gate to the active site but is rather a key feature critical to ASH1L function. We also identified a second loop in the

SUBMITTER: Rogawski DS 

PROVIDER: S-EPMC4664444 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature