Dr. Ellinor Haglund

University of Hawaii

Host: Dr. Davit Potoyan

Physcial and Theoretical Chemistry

"The Folding and Function of Proteins with Complex Topologies"

Folding of proteins into their active 3D-structure occurs spontaneously or is assisted with the help of chaperones within a biologically reasonable time, from micro- to milliseconds. It occurs within different compartments of the cell, controlled by the chemical environment. When folding goes wrong in cells, misfolded and/or aggregated proteins may arise, unable to perform their specific biological function. The correlation between structural motifs and their 3D-structure has been established to influence biology. However, less is known about the biological implications of protein topology, i.e., motifs that can act as a structural switch in response to environmental changes. Leptin is the founding member of the Pierced Lasso Topology (PLT), a newly discovered protein family sharing the unique features of a “knot-like” topology.  A PLT is formed when the protein backbone pierces through a covalent loop formed by a single disulfide bond. PLTs are found in all kingdoms of life, with 14-different biological functions, found in different cell compartments. Despite the large number found in nature, where more than 600 proteins have been found with a PLT, a connection between topology and biological function has not yet been determined. We investigate three biological systems, the hormone leptin, chemokines, and the oxidoreductase superoxide dismutase (SOD1) and the association between the threaded topology and the biological function. Our results show that a PLT may control conformational dynamics switching biological activity on/off depending on the chemical environment. Thus, we propose that PLTs may act as a molecular switch to control biological activity in vivo.

Bio:

Dr. Ellinor Haglund joined the University of Hawaii (UH) in August 2018 as an assistant professor in chemistry. Her work is focused on a combination of molecular dynamics simulations and in vitro biophysical characterization of the folding and function of proteins with a so-called Pierced Lasso Topology (PLT). A PLT is a “knot-like” topology where a covalent loop is formed in the protein backbone and part of the amino acid chain threads through this region. More than 600 proteins with PLTs have been discovered to date, represented in all kingdoms of life. Interestingly, this topology can be made and broken depending on the chemical environment. Thus, PLTs may act as biological switches turning protein activity on/off.