Marilyn Resh, PhD

The goal of my laboratory's research is to understand how fatty acylation influences the structure and function of membrane-bound signaling proteins. Our focus is on members of the Src family, a group of myristylated membrane-bound tyrosine protein kinases. My laboratory has established in vitro systems to study the biosynthesis, fatty acylation, and membrane insertion of Src kinases. We identified a novel membrane-binding motif within the Src protein consisting of myristate plus a cluster of basic residues.

Membrane association results from synergism provided by hydrophobic insertion of myristate into the lipid bilayer and electrostatic interaction of the positively charged amino acids with negatively charged head groups of acidic membrane phospholipids. This "myristate + basic" motif is also found in the Gag proteins of many retroviruses. Our laboratory showed that the myristate + basic domain mediates plasma membrane targeting of HIV-1 Gag, thereby allowing Gag to function in the formation and budding of virions. We are currently studying the molecular mechanisms involved in retroviral particle formation at the plasma membrane.

A related area of interest concerns signaling proteins modified by the 16-carbon fatty acid palmitate. We have shown that several Src-related proteins are dually fatty acylated with both myristate and palmitate. The palmitylation reaction is dynamic and reversible, and regulates the ability of Src family members to bind to membranes and participate in signaling. Our most recent experiments are focused on understanding how dual fatty acylation mediates intracellular protein trafficking, targeting to plasma membrane rafts, and intracellular signal transduction.