Senior Investigator Research Interests
Dr. Lee’s laboratory integrates a variety of biophysical and biochemical techniques to understand the molecular mechanisms of amyloid formation. Aggregation of proteins into amyloid structures is a hallmark of human diseases such as Alzheimer’s, Parkinson’s, and Hungtington’s. Interestingly, amyloid fibrils can also serve essential biological roles in organisms ranging from bacteria to humans. Moreover, many polypeptides with widely varying amino acid sequences and folded states can form amyloid in vitro, implying common formation pathways.
Dr. Lee focuses her research efforts on studying changes in protein conformation and dynamics important for the mechanisms by which amyloid structures assemble under normal and pathological conditions. A central question under investigation is: what are the distinguishing features between functional and pathological amyloids? For example, do functional amyloids aggregate such that specific pathogenic conformations are avoided? Or is the formation and degradation of amyloids regulated more efficiently in healthy cells?
To begin to understand these differences, Dr. Lee is currently investigating the mechanisms of amyloid formation for two human proteins: α-synuclein, which is localized to nerve terminals and associated with Parkinson’s disease, and Pmel17, which serves as structural scaffolding for melanin deposition in skin and eyes.
To determine the critical features guiding amyloid formation, Dr. Lee is characterizing how individual amino acid residues affect protein-protein interaction during the amyloid assembly process. A broad approach is taken to gain insights at the residue- to ultrastructural-level. Steady-state and time-resolved fluorescence and anisotropy measurements are utilized to probe local conformational changes. Protein secondary structure is determined using circular dichroism spectroscopy, and transmission electron microscopy is used to visualize filament morphology. Complementary methods, such as dynamic light scattering and atomic force microscopy, are also used. Dr. Lee is also particularly interested in the effect of metal ions and the influence of different cellular membrane compartments on protein misfolding and aggregation. Emerging methods such as neutron reflectometry are also employed to investigate protein-lipid interactions. More recently, she has studied the interaction between α-synuclein and glucocerebrosidase, the enzyme deficient in Gaucher disease, to explain why mutations in GBA, the gene encoding glucocerebrosidase, is a risk factor for Parkinsonism.
Ultimately, Dr. Lee wants to understand the mechanisms of amyloid aggregation and function at a detailed level in the context of the multiple cellular compartments with which they interact. She would like to not only describe the self-assembly process and its critical features, but also determine points of intervention in which amyloid assembly is linked to pathology.
Graphical Abstracts
Visualization of endogenous stress granules by correlative Raman and immunofluorescence imaging. A new method of correlative microscopy was developed to investigate differences in protein density in stress granules produced under oxidative stress.
Gery, K.L., Ramos, S., Lee, J.C. (2026) J. Biol. Inorg. Chem. 274, 113091. PMC12666775
Raman spectroscopy in the study of phase separation. Conformational differences in aged protein droplets can be measured by Raman spectroscopy via molecular vibrations of the protein amide backbone.
Ramos, S. & Lee, J.C. (2024) Biochem. Soc. Trans. 52, 1121-1130. PMC11346453
Spatiotemporal control of TDP-43 nuclear import. By installing a photocage on a single Lys residues through amber codon suppression, cytosolic TDP-43 can be redistributed to the nucleus via the application of light in a dose-dependent manner.
Shadish, J.R. & Lee, J.C. (2024) Biophys. Chem. 307, 107191. PMC10932890
Water bend‒libration as a cellular Raman imaging probe of hydration. Distinct water environments within subcellular compartments were visualized directly due to spectral sensitivity of the water bend-libration combination band.
Ramos, S. & Lee, J.C. (2023) Proc. Natl. Acad. Sci. U.S.A., 120, e2313133120. PMC10589711
Raman imaging of intracellular α-synuclein fibrils. Cellularly internalized α-syn fibrils were unambiguously identified by incorporating a genetically encoded, bio-orthogonal, aryl alkyne Raman probe through amber codon suppression.
Watson, M.D. & Lee, J.C. (2023) J. Mol. Biol. 435, 167716. PMC9805477
Tryptophan probes of TDP-43 C-terminal domain amyloid formation. Residue-specific information on the aggregation process of TDP-43CTD was obtained, pinpointing a distinctive role for W334 and its nearby region during aggregation.
Shuster, S.O. & Lee, J.C. (2021) J. Phys. Chem. B, 125, 3781-3789. PMC8080960
Membrane interactions of α-synuclein probed by neutrons and photons. Molecular understanding of α-synuclein membrane interactions is crucial for both physiological and pathological functions.
Kaur U. & Lee, J.C. (2021) Acc. Chem. Res. 54, 302-310. PMC7836068
Raman imaging of isotopically-labeled α-synuclein amyloids in cells. Carbon-deuterium bonds were used to resolve internalized α-synuclein fibrils from the cellular proteome.
Watson, M.D., Flynn, J.D., Lee, J.C. (2021) Biophys. Chem. 269, 106528. PMC7856057
Terminal alkynes as Raman probes of α-synuclein. Small, terminal alkynes were biosynthetically incorporated into α-synuclein as vibrational reporters, providing site-specific information on protein conformational changes in cells.
Flynn, J.D., Gimmen, M., Dean, D.N., Lacy, S.M., Lee, J.C. (2020), ChemBioChem, 21, 1582-1586. PMC7269816
N-terminal acetylation affects α-synuclein fibril polymorphism. The chemical nature of the N-terminus modulates α-synuclein aggregation, and fibril polymorphism is demonstrated by differences exhibited by thioflavin-T kinetics assay.
Watson, M.D. & Lee, J.C. (2019) N-terminal acetylation affects α-synuclein fibril polymorphism, Biochemistry, 58, 3630-3633. PMC6721997
α-Synuclein fibril structures solved by cryoelectron microscopy. Molecular differences seen in fibril structures solved by cryoelectron microscopy offer insights into the effects of C-terminal truncations on α-synuclein fibril polymorphism.
Ni, X., McGlinchey, R.P., Jiang, J., Lee, J.C. (2019) J. Mol. Biol. 431, 3913-3919. PMC6733637
Tracking region-specific conformational changes during α-synuclein aggregation. Segmentally labeled α-synuclein created by native chemical ligation contains two spectroscopically distinct amide-I bands that independently report on region-specific β-sheet structure development.
Flynn, J.D., Jiang, Z., Lee, J.C. (2018) Angew. Chem. Int. Ed. Engl. 57, 17069-17072. PMC6688611
Raman fingerprints of amyloid structures. By vibrationally “fingerprinting” a series of amyloids, distinct structural conformations can be discerned via Raman spectroscopy.
Flynn, J.D. & Lee, J.C. (2018) Chem. Commun. 54, 6983-6986. PMC6013393
Interplay between α-synuclein and phosphatidyglycerol micellar tubules. α-Synuclein is needed to stabilize the formation of phosphatidyglycerol micellar tubules, and, in turn, the micellar tubes promotes α-synuclein amyloid fibril formation.
Jiang, Z., Flynn, J.D., Teague, W.E., Gawrisch, K., Lee, J.C. (2018) Biochim. Biophys. Acta Biomembr.1860, 1840-1847. PMC6125227
Structural features of α-synuclein amyloid fibrils revealed by Raman spectroscopy. Raman spectroscopy is sensitive to subtle structural differences in α-syn fibrils that are important not only for aggregation and amyloid formation but also for disease-related mutations.
Flynn, J.D., McGlinchey, R.P., Walker III, R.L., Lee, J.C. (2018) J. Biol. Chem. 293, 767-776. PMC5777252
Mechanistic insights into α-synuclein fibril degradation by cathepsin L. Products resulting from cathepsin L degradation of α-synuclein fibrils show imperfections along the fibril axis upon close inspection of fibril morphology, with missing protein density as if they had been cannibalized.
McGlinchey, R.P., Dominah, G., Lee, J.C. (2017) Biochemistry, 56, 3881-3884. PMC5547998
Segmental deuteration of α-synuclein for neutron reflectometry on tethered bilayers. Region-specific contrast within α-synuclein was achieved by segmental deuteration, allowing for identification of N-terminal membrane-binding residues by neutron reflectometry.
Jiang, Z., Heinrich, F., McGlinchey, R.P., Gruschus, J.M., Lee, J.C. (2017) J. Phys. Chem. Lett. 8, 29-34. PMC5367044
Apolipoprotein C-III nanodiscs studied by site-specific tryptophan fluorescence. Apolipoprotein C-III remodels DMPC vesicles into HDL-like particles known as nanodiscs, where different Trp residues exhibit distinctive fluorescence properties upon lipid binding.
Brisbois, C.A. & Lee, J.C. (2016), Biochemistry, 55, 4939-4948. PMC5014578
Single particle-tracking of human lipoproteins. A new experimental framework was developed to study freely diffusing lipoproteins from human blood, allowing analysis of individual HDL, LDL, and VLDL particles in an easily constructed confinement chamber by widefield fluorescence.
de Messieres M., Ng A., Duarte, C.J., Remaley,A.T., Lee, J.C. (2016), Anal. Chem. 88, 596-599. PMC4747024
Tryptophan probes reveal residue-specific phospholipid interactions of apolipoprotein C-III. Using fluorescence measurements, information on local chemical environment, mobility, and insertion depths were obtained for individual Trp residues in apolipoprotein C-III upon lipid binding.
Pfefferkorn, C.M., Walker III, R.L., He, Y., Lee, J.C. (2015), Biochim. Biophys. Acta Biomembr. 1848, 2821-2828 PMC4598292
Molecular details of α-synuclein membrane association. Results from neutron reflectometry and fluorescence spectroscopy suggest the N- and C-terminal regions near positions 4 and 94 are anchored to the membrane, while the putative linker spanning residue 39 samples multiple conformations.
Jiang, Z., Hess, S.K., Heinrich, F., Lee, J.C. (2015), J. Phys. Chem. B, 119, 4812-4823. PMC4418488
Structural features of membrane-bound glucocerebrosidase and α-synuclein. A model of membrane-bound α-synuclein-glucocerebrosidase complex is proposed based on neutron reflectometry and other complementary techniques.
Yap, T.L., Jiang, Z., Heinrich, F., Gruschus, J.M., Pfefferkorn, C.M., Barros M., Curtis, J.E., Sidransky, E., Lee, J.C. (2015) J. Biol. Chem. 290, 744-754. PMC4295019
Lysophospholipid-containing membranes modulate the fibril formation of the repeat domain of Pmel17, a human functional amyloid. The surfactant-like lysolipids stimulate RPT aggregation kinetics and, in their micellar states, an inhibitory effect seen for LPG, whereas LPC remains stimulatory.
Jiang, Z. & Lee, J.C. (2014), J. Mol. Biol. 426, 4074-4086. PMC4258903
Molecular origin of the pH dependent fibril formation of a functional amyloid. By mutational analysis, it was determined that protonation of a single glutamic acid residue (out of the 16 carboxylic acids) is responsible for fibril formation and stability.
McGlinchey, R.P., Jiang, Z., Lee, J.C. (2014), ChemBioChem, 15, 1569-1572. PMC4142984
Membrane remodeling by α-synuclein and its effects on amyloid formation. α-Synuclein remodels zwitterionic phosphatidylcholine into membrane tubules, which inhibits fibril formation by sequestering monomers from aggregation.
Jiang, Z., de Messieres, M., Lee, J.C. (2013) J. Am. Chem. Soc. 135, 15970-15973. PMC3859146
Saposin C protects glucocerebrosidase against α-synuclein inhibition. Using nuclear magnetic resonance spectroscopy, site-specific fluorescence, and Förster energy transfer probes, Sap C was observed to displace α-syn from GCase in solution and on lipid vesicles.
Yap, T.L., Gruschus, J.M., Velayati, A., Sidransky, E., Lee, J.C. (2013) Biochemistry, 52, 7161-7163. PMC3833811
NMR structure of calmodulin complexed to an N-terminally acetylated α-synuclein peptide. Calcium-bound (holo-) CaM forms a complex with the N-terminal region of α-synuclein, whereas negligible binding was seen with apo-CaM, and the NMR structure of the complex shows that the N-terminal region adopts helical structure.
Gruschus, J.M., Yap, T.L., Pistolesi, S., Maltsev, A.S., Lee, J.C. (2013) Biochemistry 52, 3436-3445. PMC3758425
Probing fibril dissolution of the repeat domain of Pmel17, a functional amyloid. Real-time AFM measurements of RPT fibril dissolution upon solution pH neutralization shows asymmetric fibril disassembly in the absence of intermediates.
McGlinchey, R.P., Gruschus, J.M., Nagy, A., Lee, J.C. (2011) Biochemistry, 50, 10567-10569. PMC3232329
Residue-specific fluorescent probes of α-synuclein fibril assembly. Using an environmentally sensitive fluorophore, early kinetic events were revealed at the N- and C-termini for both spontaneous and seeded aggregation of α-synuclein.
Yap, T.L., Pfefferkorn, C.M., Lee, J.C. (2011) Biochemistry, 50, 1963-1965. PMC3074234
Evidence for copper-dioxygen reactivity during α-synuclein fibril formation. Copper(II)-bound α-synuclein undergoes metal reduction yielding Cu(I), and reoxidation occurs along with dityrosine formation in the presence of O2.
Lucas, H.R., DeBeer, S., Hong, M.-S., Lee, J.C. (2010), J. Am. Chem. Soc. 132, 6636-6637. PMC2880511
Meet the Team
Jennifer Lee, Ph.D.
Jennifer C. Lee graduated with a B.S. in chemistry and a B.A. in economics from the University of California, Berkeley, in 1997, and earned her Ph.D. in chemistry from the California Institute of Technology in 2002. Following a one-year postdoctoral stint at the University of Southern California, she became a Beckman Senior Research Fellow at the Beckman Institute Laser Resource Center at the California Institute of Technology where she investigated the structures and dynamics of an intrinsically disordered and amyloid forming protein using time-resolved spectroscopic measurements. In 2006, Dr. Lee joined the NHLBI as a tenure-track Investigtor. She was awarded an NIH Graduate Partnerships Program Outstanding Mentor Award in 2009. Dr. Lee is a member of the American Chemical Society and the Protein Society.
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Matthew Watson, Ph.D.
Ryan McGlinchey, Ph.D.
Sashary Ramos, Ph.D.
Kevin Gery
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