Membrane Protein Structure and Function
Overview:
Our lab is interested in studying the grey area of various disease-related membrane proteins. More specifically, we are interested in how the structure of membrane proteins contributes to disease pathogenesis. This structural information can give mechanistic insights into disease progression and intervention. We thus aim to identify the structure-to-function relationships of these proteins using biochemical and biophysical techniques. Select a link below for more details on the ongoing projects within our lab!
- Lassa Virus Membrane Fusion
In recent decades, we have seen several infectious disease outbreaks caused by viruses, including human immunodeficiency virus (HIV), influenza, and Ebola virus (EBOV). Now, given the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, there is a glaring necessity to study emerging viruses in preparation for the next pandemic. Lassa virus (LASV), an arenavirus endemic to West Africa, is the most prevalent arenavirus afflicting humans. It is spread via direct contact with the excrement of infected Mastomys natalensis rodents and, rarely, between humans by bodily fluids. Infection with LASV causes Lassa fever, a viral hemorrhagic fever with high morbidity and mortality that affects an estimated 100,000 to 300,000 individuals annually. A recent outbreak of LASV had a case fatality rate (CFR) of 20.5%. In fact, the World Health Organization lists LASV as an infectious disease requiring prioritized research due to its threat to public health. There are currently no FDA-approved vaccines or antivirals for the explicit treatment of Lassa fever. Thus, an improved understanding of LASV is necessary to develop better therapeutic interventions.
We aim to investigate the structure and function of the LASV glycoprotein complex (GPC). This is the only protein located on the viral envelope and is ultimately responsible for viral membrane fusion – a step integral to viral survival in the host cell. Our projects involve researching the various proteins involved in this fusion event, including the fusion peptide, transmembrane domain of glycoprotein 2, and stable signal peptide. The information we gain will not only further our understanding of the LASV membrane fusion mechanism but will also illuminate a new target for drug design.
- SARS-CoV-2 Membrane Fusion
Following the outbreak of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, the threat of the coronavirus family had already been well established. Yet, the rapid emergence and remarkable infectivity of SARS-CoV-2, the causative agent of COVID-19, has resulted in a global pandemic of incredible magnitude. With nearly 200 million people infected and over 4 million deaths, the importance of elucidating the underlying mechanisms behind pathogenic viruses has never been more prevalent than now. While several vaccines have been developed to combat the ongoing pandemic, there is no guarantee that those treatments will prove to be effective against variants of SARS-CoV-2.
Membrane fusion is a vital process in the virus life cycle, which allows the virus to deliver its genetic information into the host cell. The spike (S) glycoprotein found on the viral surface is the primary antigenic determinant of the coronavirus family and is responsible for facilitating membrane fusion. However, the structure and function of the spike protein is not entirely understood with major components yet to be fully characterized. We aim to investigate the structural arrangement of the SARS-CoV-2 fusion peptide to further our understanding of fusion. The information we gain may also help in the development of antiviral drugs targeting SARS-CoV-2.
- Podocin’s Intramembrane Domain
The major function of the kidney is to filter our blood to remove waste while retaining any useful macromolecules. This filtration occurs in the Bowman capsule of the glomerulus where extensions of podocytes, called foot processes, cover the capillaries of the glomerulus. The spaces between the podocyte foot processes are comprised of slit diaphragms (SD) that form the matrix for filtration. The SD is composed of a nephrin/podocin/CD2AP protein complex. Podocin is a crucial member of this complex; however, it is not clear how the unusual hairpin domain of podocin contributes to its critical functions. To elucidate the detailed functions of the unusual hairpin intramembrane domain of podocin, we aim to use biochemical/biophysical and structural studies of podocin in the lipid bilayer to investigate its function.
- Magnetosome Associated Membrane Protein
Magnetotactic bacteria are Gram-negative bacteria with the ability to use geomagnetic fields for navigating. This ability is governed by magnetosomes, which are magnetite (Fe3O4)-containing vesicles. To understand this mechanism, we are examining the structure and function of the proteins that control the size and shape of the magnetic particles in the presence of a lipid bilayer. Many magnetic particle applications are possible including catalysis, magnetic storage, targeted drug delivery, cancer therapy, and magnetic resonance imaging (MRI). These processes can benefit tremendously from more precisely controlled magnetic particle generation.