Through the H.L. Holmes Award, the NRC supports innovative postdoctoral research that could lead to major advances in the understanding of many neurobiological diseases

Exploring the functional dynamics of proteins as a graduate student at the University of Toronto

The structures and motions of proteins determine their functions. Aberrant changes in protein structure or dynamics result in diseases. Although atomic-resolution structures provide a static 3D view of protein molecules, these structures alone are not enough to understand the molecular details of protein function. Dynamics are also now widely recognized as a key determinant of protein function. Insight into protein dynamics is essential for understanding diseases and developing therapeutics, because we can't cure something we don't understand. During his Ph.D. training, Dr. Kim investigated the functional dynamics of two proteins, β₂-adrenergic receptor and fluoroacetate dehalogenase, under the supervision of Prof. R. Scott Prosser at the University of Toronto and in collaborations with Prof. Brian K. Kobilka (Stanford University, 2012 Nobel prize in Chemistry) and Prof. Emil F. Pai (University of Toronto). During the course of the projects, Dr. Kim discovered the mechanisms for understanding how different drugs influence the structures and dynamics of these two proteins. These findings lead to five first-authored publications in prestigious journals like Cell, Science, the Journal of American Chemistry Society, and the Journal of Biological Chemistry.

The study of disordered proteins and their interactions in liquid-liquid phase separation, a promising novel approach for the study of neurological diseases

Although the human brain is still very poorly understood, the treatment of neurological diseases such as autism or Alzheimer's is one of the greatest medical challenges of our societies. It is also a growing challenge, as our population is aging, and more and more people are falling prey to neurological diseases1. It is therefore urgent to support neurobiological research focused on understanding the phenomena related to these diseases.

Under the supervision of Prof. Julie D. Forman-Kay (Hospital for Sick Children) and Prof. Lewis E. Kay (University of Toronto), Dr. Kim will take up this challenge by studying one of the recently discovered phenomena that would be involved in the development of neurobiological diseases: the disruption of the interactions of disordered proteins, especially with RNA in liquid-liquid separations, due to a dysfunction of these proteins. Intrinsically disordered proteins are long molecules that have "flexible" portions, unlike the usual molecular formations that are very stable. They interact, among other things, with RNA, which "copies" a portion of deoxyribonucleic acid (DNA), and thus allows for the expression of genes. Most of these interactions take place by a mechanism called 'liquid-liquid phase separation'. They occur in membrane-less organelles, i.e. sets of molecules that act within the cell as mini-organisms and help the proper functioning and regulation of the cells. This phenomenon, mainly involving "disordered" proteins and their interactions with RNA, would have a strong link with neuronal functions and therefore with the development of neurological diseases.

To explore in detail the role of disordered proteins and their interactions in liquid-liquid phase separation, Dr. Kim proposes to study the specific case of the disordered portion of the CAPRIN1 protein, involved in neurological functions and more particularly in diseases such as autism. The disordered portion of the CAPRIN1 protein would play an important role in the triggering a liquid-liquid separation phase. But it is also proven that this normally constituted molecule ensures the proper functioning of neurons. Thus, by studying this protein through a new nuclear magnetic resonance method—a method of visualizing atomic structures—developed in his postdoctoral research laboratories at the Hospital for Sick Children and University of Toronto, Dr. Kim would be able to obtain radically more precise and complex data on this separation phase as well as on the disordered regions of proteins. CAPRIN1 is a perfect candidate protein for obtaining structural and biophysical data on separation phases.

By leveraging new technologies and this multidisciplinary approach, Dr. Kim could potentially revolutionize our understanding of the interactions between disordered proteins and RNA. In view of their important role in neurobiological functions and liquid-liquid phase separation, this novel approach focusing on disordered proteins opens up new avenues in the study of neurological diseases.

"I am delighted to be the recipient of the 2019 Holmes Award", he explains. "This award will empower my scientific endeavour to investigate the disease-relevant states of proteins, nucleic acids, and their complexes. I was able to achieve my scientific accomplishments under the guidance of my Ph.D. and postdoctoral advisors. I am truly grateful for their support, and patience."

The H.L. Holmes Award

The H.L. Holmes Award has been established by the National Research Council of Canada (NRC) in honour of the late Dr. R.H.L. Holmes, a chemist who spent most of his research career in Alberta.

Bequeathed by the late Dr. Holmes, in recognition of NRC's commitment to promote research excellence, the award gives recipients the opportunity to conduct post-doctoral studies under outstanding researchers at world-famous graduate schools or research institutes. Research must be undertaken in chemistry, physics, biology or mathematics as they relate to medical and biological processes.