The Laboratory of Protein Conformation and Dynamics integrates complementary biophysical and biochemical techniques to understand the molecular mechanisms of amyloid formation.
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.
Shuster, S.O. & Lee, J.C. (2021) Tryptophan probes of TDP-43 C-terminal domain amyloid formation, J. Phys. Chem. B., 125, 3781-3789. DOI: 10.1021/acs.jpcb.1c00767
Kaur U. & Lee, J.C. (2021) Membrane interactions of α-synuclein probed by neutrons and photons, Acc. Chem. Res. 54, 302-310. DOI: 10.1021/acs.accounts.0c00453
Watson, M.D., Flynn, J.D., Lee, J.C. (2021) Raman spectral imaging of 13C2H15N-labeled α-synuclein amyloid fibrils in cells, Biophys. Chem. 269, 106528. DOI: 10.1016/j.bpc.2020.106528
Flynn, J.D., Gimmen, M., Dean, D.N., Lacy, S.M., Lee, J.C. (2020) Terminal alkynes as Raman probes of α-synuclein in solution and in cells, ChemBioChem, 21, 1582-1586. DOI: 10.1002/cbic.202000026
Watson, M.D. & Lee, J.C. (2019) N-terminal acetylation affects α-synuclein fibril polymorphism, Biochemistry, 58, 3630-3633. DOI: 10.1021/acs.biochem.9b00629
Ni, X., McGlinchey, R.P., Jiang, J., Lee, J.C. (2019) Structural insights into α-synuclein fibril polymorphism: Effects of Parkinson’s disease-related C-terminal truncations, J. Mol. Biol. 431, 3913-3919. DOI: 10.1016/j.jmb.2019.07.001
Flynn, J.D., Jiang, Z., Lee, J.C. (2018) Segmental 13C-labeling and Raman microspectroscopy of α-synuclein amyloid formation, Angew. Chem. Int. Ed. Engl. 57, 17069-17072. DOI: 10.1002/anie.201809865
Flynn, J.D. & Lee, J.C. (2018) Raman fingerprints of amyloid structures, Chem. Commun. 54, 6983-6986. DOI: 10.1039/c8cc03217c
Jiang, Z., Flynn, J.D., Teague, W.E., Gawrisch, K., Lee, J.C. (2018) Stimulation of α-synuclein amyloid formation by phosphatidyglycerol micellar tubules, Biochim. Biophys. Acta Biomembr.1860, 1840-1847. DOI:10.1016/j.bbamem.2018.02.025
Flynn, J.D., McGlinchey, R.P., Walker III, R.L., Lee, J.C. (2018) Structural features of α-synuclein amyloid fibrils revealed by Raman spectroscopy, J. Biol. Chem. 293, 767-776. DOI:10.1074/jbc.M117.812388
McGlinchey, R.P., Dominah, G., Lee, J.C. (2017) Taking a bite out of amyloid: Mechanistic insights into α-synuclein degradation by cathepsin L, Biochemistry, 56, 3881-3884. DOI: 10.1021/acs.biochem.7b00360
Jiang, Z., Heinrich, F., McGlinchey, R.P., Gruschus, J.M., Lee, J.C. (2017) Segmental deuteration of α-synuclein for neutron reflectometry on tethered bilayers, J. Phys. Chem. Lett. 8, 29-34. DOI: 10.1021/acs.jpclett.6b02304
Brisbois, C.A. & Lee, J.C. (2016) Apolipoprotein C-III nanodiscs studied by site-specific tryptophan fluorescence, Biochemistry, 55, 4939-4948. DOI: 10.1021/acs.biochem.6b00599
de Messieres M., Ng A., Duarte, C.J., Remaley, A.T., Lee, J.C. (2016) Single particle-tracking of human lipoproteins, Anal. Chem. 88, 596-599. DOI: 10.1021/acs.analchem.5b03749
Pfefferkorn, C.M., Walker III, R.L., He, Y., Lee, J.C. (2015) Tryptophan probes reveal residue-specific phospholipid interactions of apolipoprotein C-III, Biochim. Biophys. Acta Biomembr.,1848, 2821-2828. DOI: 10.1016/j.bbamem.2015.08.018
Jiang, Z., Hess, S.K., Heinrich, F., Lee, J.C. (2015) Molecular details of α-synuclein membrane association probed by neutrons and photons, J. Phys. Chem. B 119, 4812-4823. DOI: 10.1021/jp512499r
Yap, T.L., Jiang, Z., Heinrich, F., Gruschus, J.M., Pfefferkorn, C.M., Barros M., Curtis, J.E., Sidransky, E., Lee, J.C. (2015) Structural features of membrane-bound glucocerebrosidase and α-synuclein probed by neutron reflectometry and fluorescence spectroscopy, J. Biol. Chem. 290, 744-754. DOI: 10.1074/jbc.M114.610584
Jiang, Z. & Lee, J.C. (2014) Lysophospholipid-containing membranes modulate the fibril formation of the repeat domain of a human functional amyloid, Pmel17, J. Mol. Biol. 426, 4074-4086. DOI: 10.1016/j.jmb.2014.10.009
McGlinchey, R.P., Jiang, Z., Lee, J.C. (2014) Molecular origin of the pH dependent fibril formation of a functional amyloid, ChemBioChem, 15, 1569-1572. DOI: 10.1002/cbic.201402074
Jiang, Z., de Messieres, M., Lee, J.C. (2013) Membrane remodeling by α-synuclein and effects on amyloid formation, J. Am. Chem. Soc. 135, 15970-15973. DOI: 10.1021/ja405993r
Yap, T.L., Gruschus, J.M., Velayati, A., Sidransky, E., Lee, J.C. (2013) Saposin C protects glucocerebrosidase against α-synuclein inhibition, Biochemistry 52, 7161-7163. DOI: 10.1021/bi401191v
Gruschus, J.M., Yap, T.L., Pistolesi, S., Maltsev, A.S., Lee, J.C. (2013) NMR structure of calmodulin complexed to an N-terminally acetylated α-synuclein peptide, Biochemistry 52, 3436-3445.
McGlinchey, R.P., Gruschus, J.M., Nagy, A., Lee, J.C. (2011) Probing fibril dissolution of the repeat domain of a functional amyloid, Pmel17, on the microscopic and residue level, Biochemistry 50, 10567-10569. DOI: 10.1021/bi201578h
Yap, T.L., Pfefferkorn, C.M., Lee, J.C. (2011) Residue-specific fluorescent probes of α-synuclein: Detection of early events at the N- and C-termini during fibril assembly, Biochemistry 50, 1963-1965. DOI: 10.1021/bi2000824
Lucas, H.R., DeBeer, S., Hong, M.-S., Lee, J.C. (2010) Evidence for copper-dioxygen reactivity during α-synuclein fibril formation, J. Am. Chem. Soc. 132, 6636-6637.DOI: 10.1021/ja101756m
Pfefferkorn, C.M. & Lee, J.C. (2010) Tryptophan probes at the α-synuclein and membrane interface, J. Phys. Chem. B. 114, 4615-4622. DOI: 10.1021/jp908092e
Petrik, A.F., Strub, M.-P., Lee, J.C. (2010) Energy transfer probes of GluR2 ligand binding core, Biochemistry 49, 2051-2057. DOI: 10.1021/bi9020007
Jackson, M.S. & Lee, J.C. (2009) Identification of the minimal copper(II)-binding α-synuclein sequence, Inorg. Chem. 48, 9303-9307. DOI: 10.1021/ic901157w
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.