Functional proteomics

Studying the Function of Lysine Methylation 


Systematic exploration of enzyme substrates to study their role in disease progression

The growing realization that lysine methylation plays a critical role in the development of many human diseases is perhaps not a surprising one. Dysfunction in the dynamic lysine methylation network (currently consisting of >5000 different lysine methylation modifications) has been identified as a prominent contributor to the development of many different types of cancer. For example, one pivotal study unveiled that the methyltransferase SMYD3 enhances the progression of Ras-driven leukemia through the methylation of the MAP3K2 protein at lysine 260. Given the involvement of lysine methylation in a growing number of different biological processes, it is now critical that we understand how these methyltransferase function and ID the proteins that they methylate.

We use synthesize  peptide arrays to ID the sequence of amino acids that are necessary for an enzyme to recognize and methylate its substrate.  With this information, we can work to identify in vivo enzyme substrates to build the enzyme-substrate network and help to establish the cellular roles of methyltransferase enzymes.

Quantitative proteomic technologies to study lysine modification pathways

Lysine is an important target of protein modifications playing key roles in the epigenetic regulation, cell signaling and protein degradation. Lysine methylation is an ancient protein modification first discovered in 1959. Recently, the MS-based global analysis of the methyllysine proteome revealed multi-faceted roles of lysine methylation in regulating gene transcription, signal transduction, enzyme activity and cellular metabolism. Based on the success of this technology platform, we are combining quantitative proteomics technology to identify lysine methylation targets of the regulatory enzymes and the dynamics of the methyllysine proteome in response to cellular hypoxia. We are also developing new systematic strategies to determine the site-specificity of lysine methyltransferase and demethylase enzymes to help discover the methylation enzyme-substrate network.
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