Degree Type

Honors Capstone Project

Date of Submission

Spring 5-1-2014

Capstone Advisor

Dr. Michael Cosgrove

Honors Reader

Dr. Stephen Dorus

Capstone Major


Capstone College

Arts and Science

Audio/Visual Component


Capstone Prize Winner


Won Capstone Funding


Honors Categories

Sciences and Engineering

Subject Categories

Biochemistry | Biochemistry, Biophysics, and Structural Biology


Methylation at histone H3 lysine 4 (H3K4) is a post-translational modification often associated with transcriptional regulation through altering the structural state of chromatin. The human mixed lineage leukemia protein-1 protein (MLL1) is a known histone methyltransferase that catalyzes the transfer of methyl groups to H3K4. MLL1 works in a core complex with other essential components, proteins WDR5, RbBP5, Ash2L, DPY-30 (WRAD), which is required for H3K4 dimethylation. Trithorax (TRX) protein is the Drosophila melanogaster ortholog to human MLL1, and although structurally similar is unable to perform dimethylation when in complex with the human components. The goal of this study is to understand the structural basis for this difference. We systematically mutated 20 amino acids in TRX the equivalent amino acid in human MLL1 and tested for a gain-of-function H3K4 dimethylation activity. We found 20 amino acid positions in TRX that were highly conserved among intertebrates but were different in vertebrates. Out of the 20 amino acids mutated, 5 showed a gain of dimethylation activity. All of the mutations that showed a gain of dimethylation activity localized to a common SET domain surface. The identified mutations on the common surface identify a location of the dimethyltransferase active site on MLL1.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

Included in

Biochemistry Commons



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