Justin Legleiter, Ph.D.

Professor - Coordinator of the Undergraduate Intercollegiate Biochemistry Program

Legleiter Group website - Intercollegiate Biochemistry Program website

About

Dr. Legleiter earned his bachelor’s degree in Chemistry (2000) at Murray State University (Murray, KY) and his PhD in Chemistry (2005) at Carnegie Mellon University (Pittsburgh, PA) under the supervision of Dr. Tomasz Kowalewski. He then spent three years at the Gladstone Institute of Neurological Disease at the University of California, San Francisco as a postdoctoral fellow in the lab of Dr. Paul Muchowski. In August of 2008, he moved to West Virginia University as an assistant professor in the C. Eugene Bennett Department of Chemistry.

There are a large and diverse number of diseases that are commonly classified as conformational diseases. The common feature of these diseases is the rearrangement of a specific protein to a non-native conformation that promotes aggregation and deposition within tissues and/or cellular compartments. Such diseases include Alzheimers disease, Huntingtons disease, Parkinsons disease, amyloidoses, the prion encephalopathies, and many more. A common structural motif in the majority of these diseases is the emergence of extended, -sheet rich, proteinaceous fibrillar aggregates that are commonly referred to as amyloids. These fibrillar species are comprised of intertwined protofibrillar filaments, which often have globular, soluble protein aggregate precursors, more commonly referred to as oligomers. For the vast majority of these diseases, there are no widely effective preventative or therapeutic treatments. The major research goal of our laboratory is to understand the molecular mechanisms that underlie neurodegenerative disorders associated with protein misfolding and aggregation, with a focus on Alzheimers disease and Huntingtons disease. In particular, we are interested in the potential role cellular and subcellular surfaces may play in these events.

We utilize a broad array of research tools and biochemical methods in our studies, but our primary tool is the atomic force microscope (AFM). AFM has provided particularly useful insights related to conformational disease due to its unique ability to be operated not only in air (ex situ) but also in solution (in situ), making it possible to directly visualize the behavior of biological macromolecules at solid-liquid interfaces, under nearly physiological conditions. The ultimate objective of our amyloidogenic peptide AFM studies is to elucidate the physiochemical aspects and molecular mechanisms of pathological self-assembly of biological macromolecules that lead to toxicity..

Teaching Fields

Physical Chemistry

Courses Offered

CHEM 348 - Physical Chemistry II
CHEM 348L - Physical Chemistry II Laboratory
graduate courses in biophysical chemistry and proximal probe techniques

Selected Publications

Legleiter, J., Thakkar, R., Velásquez-Silva, A., Miranda-Carvajal, I., Whitaker, S., Tomich, J., Comer, J. Design of Peptides that Fold and Self-Assemble on Graphite. Journal of Chemical Information and Modeling (2022).

Adegbuyiro, A., Stonebraker, A.R., Sedighi, F., Fan, C.K.*, Hodges, B.*, Li, P., Valentine, S.J., Legleiter, J. Oxidation Promotes Distinct Huntingtin Aggregates in the Presence and Absence of Membranes. Biochemistry (2022) 61, 1517–1530.

Beasley, M., Frazee, N., Groover, S., Valentine, S.J., Mertz, B., Legleiter, J. Physicochemical Properties Altered by the Tail Group of Lipid Membranes Influence Huntingtin Aggregation and Lipid Binding. The Journal of Physical Chemistry B (2022) 126, 3067–3081.

Groover S.E., Legleiter J., and Battin E.E. Huntingtin Protein Purification and Experimentation: An Innovative Undergraduate Research-Based Biochemistry Experiment. Journal of Chemical Education (2021) 98:3011-3018.

Groover S.E., Adegbuyiro A., Fan C.K., Hodges B.L., Beasley M., Taylor K., Stonebraker A.R., Siriwardhana C., and Legleiter J. Macromolecular crowding in solution alters huntingtin interaction and aggregation at interfaces. Journal of Colloids and Surfaces B: Biomembranes (2021) 206:111969.

Adegbuyiro A., Sedighi F., Pranav J., Pinti M.V., Siriwardhana C., Hollander J.M., and Legleiter J. Mitochondrial membranes modify mutant huntingtin aggregation. Biochimica et Biophysica Acta (BBA) – Biomembranes (2021) 1863:183663.

Beasley M., Groover S.E., Valentine S., and Legleiter J. Lipid headgroups alter huntingtin aggregation on membranes. Biochimica et Biophysica Acta (BBA) – Biomembranes (2021) 1863:183497.

Groover S.E., Beasley M., Ramamurthy V., and Legleiter J. Phosphomimetic Mutations Impact Huntingtin Aggregation in the Presence of a Variety of Lipid Systems. Biochemistry (2020) 59:4681-4693.

Beasley M., Stonebraker A.R., and Legleiter J. Normalizing Polydiacetylene Colorimetric Assays of Vesicle Binding Across Lipid Systems. Analytical Biochemistry (2020) 609:113864.

Sedighi F., Adegibuyiro A., and Legleiter J. SUMOylation of huntingtin prevents fibrillization and localization onto lipid membranes. ACS Chemical Neuroscience (2020) 11:328−343.

Arndt J.R., Chaibva M., Kondalaji S.G., Khakinejad M., Sarver O., Legleiter J., and Valentine S.J. Nucleation inhibition of Huntingtin protein (htt) by polyproline PPII helices: a potential interaction with the N-terminal α-helical region of htt. Biochemistry (2020) 59:436-449.

Pilkington A.W. IV, Nyman M., Valentine S.J., and Legleiter J. Acetylation of Aβ40 alters aggregation in the presence and absence of lipid membranes. ACS Chemical Neuroscience (2020) 11:146−161.

Karanji A.K., Beasley M., Sharif D., Ranjbaran A., Legleiter J., and Valentine S.J. Investigating the interactions of the first 17 amino acid residues of Huntingtin with lipid vesicles using mass spectrometry and molecular dynamics. J. Mass Spectrom. (2019) 1-13.

Beasley M., Stonebraker A., Hassan I., Kapp K., Leung B., Agarwal G., Groover S., Sedighi F., and Legleiter J. Lipid membranes influence the ability of small molecules to inhibit huntingtin fibrillization. Biochemistry (2019) 58:4361-4373.

Pilkington A.W. IV, Donohoe G.C., Akhmedov N.G., Ferrebee T., Valentine S.J., and Legleiter J. Hydrogen Peroxide Modifies Aβ–Membrane Interactions with Implications for Aβ40 Aggregation. Biochemistry (2019) 58:2893-2905.

Pilkington A.W. IV and Legleiter J. Challenges in understanding the structure/activity relationship of Aβ oligomers. AIMS Biophysics (2019) 6:1-22.

Chaibva M., Gao X., Jain P., Campbell IV W.A., Frey S.L., and Legleiter J. Sphingomyelin and GM1 Influence Huntingtin Binding to, Disruption of, and Aggregation on Lipid Membranes. ACS Omega (2018) 3:273-285.

Kumar B., Miller K., Charon N.W., and Legleiter J. Periplasmic flagella in Borrelia burgdoferi function to maintain cellular integrity upon external stress. PLoS ONE (2017) 12:e0184648.

Adegbuyiro A., Sedighi F., Pilkington A.W. IV, Groover S., and Legleiter J. Proteins containing expanded polyglutamine tracts and neurodegenerative disease. Biochemistry (2017) 56:1199-1217.