Daniel C. Masison, Ph.D.

Our goal is to understand how protein chaperones and co-chaperones function at a molecular level. We want to understand their intrinsic functions and how they cooperate, regulate and fine-tune each other’s activities, as well as how their activities help maintain normal protein homeostasis and influence various aspects of amyloid propagation in cells.

Current Research

We use genetics, molecular biology, and biochemistry to identify and characterize cellular factors that influence propagation of disease-causing amyloid in yeast. The amyloid-forming proteins we study have a propensity to misfold and form highly structured fibrous amyloid aggregates. Tissue pathology in many human disorders, including type 2 diabetes Huntington’s and Alzheimer’s diseases, is associated with accumulation of amyloid forms of proteins. They can be transmissible between cells and they propagate by recruiting the normal form of the protein and converting it into the same misshapen form as it joins the growing fiber.

Hsp70 is a universally conserved and essential protein chaperone that helps proteins adopt and maintain their native structural conformations. Hsp70 activity is regulated by co-chaperones, such as J-proteins. By acting on amyloid as a misfolded target, the normal functions of this and other chaperone machinery can counteract amyloid toxicity, yet promote amyloid propagation by breaking fibers into more numerous pieces. We have identified several mutations in these chaperones that variously affect amyloid seeding, assembly, and replication processes. Determining how these mutations affect the chaperones’ activities and ability to interact with each other will help us understand the molecular mechanisms underlying the anti-amyloid functions of this machinery.

We have also found that TPR co-chaperones, which are components of the Hsp90 machinery, can regulate Hsp70 function independently of Hsp90. We are also using our system to dissect the mechanisms of how these co-chaperones regulate Hsp70 and Hsp90 activity, and for assessing in vivo functions of Hsp90.

We have identified many mutants of various protein chaperones, in particular Hsp70, Hsp90 and their co-chaperones, that are revealing chaperone and co-chaperone interactions that are important for crucial cellular processes as well as influencing amyloid. We are continuing genetic and biochemical characterization of the modified chaperones and working to define how the mutations affect their physical interactions and enzymatic activities. We are particularly interested in understanding how the various chaperones interact with each other to regulate each other’s functions and to cooperate as components of different protein remodeling machines. We also are working to understand how specific interactions among the many different components act to localize, direct, and fine-tune the chaperone machinery in its diverse cellular processes. Many of the chaperone "defects" that disrupt amyloid propagation have little or no effect on cell physiology, which points to these proteins as attractive targets for therapy in amyloid diseases. In addition to providing a better understanding of how protein chaperones function in amyloid propagation, our continued studies will provide insight into how they act in their many important and essential roles within the cell.

Applying our Research

By understanding the molecular interactions that influence propagation of amyloid, our work might help in developing strategies to combat it.

• Ph.D., University of Massachusetts Medical Center, 1993
• B.S., University of Massachusetts, 1983