Guy Benian, PhD

Professor

Department of Cell Biology

Professor

Department of Pathology and Laboratory Medicine

Office: 105E Whitehead Research Building

Phone: 404-727-5953

Email: pathgb@emory.edu

Office Location:

Mailing Address:

Emory University - Department of Cell Biology

615 Michael St. Atlanta, GA 30322 1941-001-1AC

Atlanta, GA 30322

Research Focus

The sarcomere performs the work of muscle contraction and is a highly ordered assemblage of several hundred proteins. Despite increasing knowledge of the components and functions of sarcomeric proteins (new ones are discovered each year!), we still don't understand how sarcomeres are assembled, and maintained. Our lab is studying these questions in the model genetic organism, C. elegans. We focus on two questions: (1) What are the structures and functions of the giant muscle proteins (>700,000 Da)? (2) What are the molecular mechanisms by which sarcomeres are attached to the muscle cell membrane and transmit force? The giant muscle proteins consist primarily of multiple copies of immunoglobulin (Ig) and fibronectin type 3 (Fn3) domains, and one or even two protein kinase domains. C. elegans has 3 such proteins: twitchin (754,000 Da, located in the A-band, and probably regulating muscle relaxation), TTN-1 (2.2 MDa, located in the I-band and perhaps acting as a molecular spring), and UNC-89 (up to 900,000 Da, a homolog of the human protein "obscurin", and having roles in M-line assembly and integration with the SR). 

We are making progress in identifying proteins that interact with these giants that explains their localization and their functions, especially for UNC-89. One of the proteins that we found interacts with UNC-89 is MEL-26, and adaptor protein for cullin 3. As cullins act as scaffolds for assembly of the ubiquitin protein degradation machinery, UNC-89 is implicated in a novel mode of regulating protein degradation is muscle. Other goals include learning the substrates of the protein kinase domains, and to understand how the normally "autoinhibited" kinase domains become activated. Our current model is that kinase activation is a multi-step process involving phosphorylation, binding to other proteins and small pulling forces (~10-20 pN) that normally occur during muscle activity. Evidence for the importance of mechanical force in activation is being pursued through collaboration with structural biologists, biophysicists and biomedical engineers. By cloning mutationally-defined genes, conducting 2-hybrid screens, and localizing proteins with antibodies and GFP fusions, we are defining complex protein interaction networks at muscle attachment sites. We are testing the hypothesis that proteins at the attachment sites are involved in transmitting the force of muscle contraction to the outside of the cell. Another project is to test the hypothesis that the localization of one of these proteins, UNC-112 (kindlin in humans), is regulated by an interaction with PAT-4 (ILK), which promotes a conformational change in UNC-112. We have biochemical and genetic evidence for this conformational change; we are currently trying to obtain biophysical evidence.

Publications