Maintaining the proper three-dimensional structure, concentration, activity, and localization of proteins is a critical and constant challenge for all organisms. Dysregulated protein homeostasis is inextricably linked to disease states. Accordingly, the most prominent diseases of modern times—including neurodegenerative diseases like Alzheimer’s disease, diabetes, loss-of-function diseases like cystic fibrosis, many types of cancer, and even viral infections—are either caused directly by a failure to maintain protein homeostasis or reliant on innate cellular protein folding mechanisms. Proteome repair achieved by targeting the cellular mechanisms that regulate protein folding could transform the therapeutic options for broad swaths of protein folding-related disease. Critically, methods to intervene in a single important protein folding pathway could be applied to multiple, diverse pathologies.
Before proteome repair can mature as a therapeutic strategy, we must learn much more about how proteins fold in the cell and about the specific cellular mechanisms we can exploit to rescue pathologic protein folding problems without globally disrupting cell health. Few selective chemical and chemical biologic tools currently exist to explore these issues in vivo. The Shoulders Laboratory is focused on integrating the tools of chemistry and biology to elucidate the complex pathways responsible for maintaining cellular protein homeostasis. Our lab employs a multi-disciplinary approach to (1) understand at the molecular level how the cell remodels itself to address challenges to protein homeostasis, (2) elucidate the pathophysiology of protein folding-related diseases with poorly defined etiologies, and (3) target the biological processes we uncover for the development of new small molecule probes, tools, and (ultimately) drugs.
We are particularly interested in developing and applying chemical biology tools and bioorthogonal chemistry to elucidate how cells dynamically adjust the molecular identities of proteins in response to dysregulated protein homeostasis. In this area, our initial focus is on cancer-related and stress-induced post-translational protein modifications—such as N- and O-glycosylation. We also work to understand the etiologies of and develop new therapeutic strategies for incurable orphan diseases that derive from missense mutations to extracellular matrix proteins, such as osteogenesis imperfecta. These disorders are powerful models for entire categories of protein folding-related diseases. As we discover and characterize pathways involved in cellular protein folding, we also develop new chemical entities that modulate those pathways for the treatment of protein folding-related diseases.
Members of the Shoulders lab gain expertise in organic chemistry, biochemistry, biophysics, and cell biology in an atmosphere that promotes creativity and bold ideas. We employ a wide range of experimental techniques including chemical synthesis, molecular biology, peptide and protein preparation and purification, tissue culture, spectroscopy and biophysical measurements (IR, UV-Vis, NMR, CD, AUC, DSC, DLS, ITC, MS), microscopy, and high-throughput assay development.
Interested postdoctoral candidates should email a cover letter, CV, and list of three references directly to Dr. Shoulders.
Shoulders, M.D.; Ryno, L.M.; Kelly, J.W.; Wiseman, R.L. "Broadly Applicable Methodology for the Rapid and Dosable Small Molecule-Mediated Regulation of Transcription Factors in Human Cells" Journal of the American Chemical Society 2013, in press.
Shoulders, M.D.; Ryno, L.M.; Genereux, J.C.; Moresco, J.J.; Tu, P.G.; Wu, C.; Yates, J.R. III; Su, A.I.; Kelly, J.W.; Wiseman, R.L. "Stress-Independent Activation of XBP1s and/or ATF6 Reveals Three Functionally Diverse Endoplasmic Reticulum Proteostasis Environments" Cell Reports 2013, 3, 1279-1292.
Krow, G.R.; Shoulders, M.D.; Edupuganti, R.; Gandla, D.; Yu, F.; Sonnet, P.E.; Sender, M.; Choudhary, A.; DeBrosse, C.; Ross, C.W., III; Carroll, P.; Raines, R.T. “Synthesis of 5-Fluoro- and 5-Hydroxymethanoprolines via Lithiation of N-BOC-Methanopyrrolidines. Constrained Cγ-Exo and Cγ-Endo Flp and Hyp Conformer Mimics” Journal of Organic Chemistry 2012, 77, 5331-5344.
Shoulders, M.D.; Raines, R.T. “Interstrand Dipole-Dipole Interactions Can Stabilize the Collagen Triple Helix” Journal of Biological Chemistry 2011, 286, 22905–22912.
Krow, G.R.; Edupuganti, R.; Gandla, D.; Yu, F.; Sender, M.; Sonnet, P.E.; Zdilla, M.J.; DeBrosse, C.; Cannon, K.C.; Ross, C.W., III; Choudhary, A.; Shoulders, M.D.; Raines, R.T. “Synthesis of Conformationally Constrained 5-Fluoro- and 5-Hydroxymethanopyrrolidines. Ring Puckered Mimics of Gauche and Anti-3-Fluoro- and 3-Hydroxypyrrolidines” Journal of Organic Chemistry 2011, 76, 3626–3634.
Shoulders, M.D.; Kotch F.W.; Choudhary, A.; Guzei, I.A.; Raines, R.T. "The Aberrance of the 4S Diastereomer of 4-Hydroxyproline" Journal of the American Chemical Society, 2010, 132, 10857–10865.
Shoulders, M.D.; Satyshur, K.A.; Forest, K.T.; Raines, R.T. "Stereoelectronic and Steric Effects in Side Chains Preorganize a Protein Main Chain" Proceedings of the National Academy of Sciences, USA 2010, 107, 559–564.
Krow, G.R.; Liu, N.; Sender, M.; Lin, G.; Centafont, R.; Sonnet, P.E.; DeBrosse, C.; Ross, C.W., III; Carroll, P.J.; Shoulders, M.D.; Raines, R.T. “Oligomers of a 5-Carboxymethanopyrrolidine β-Amino Acid—A Search for Order” Organic Letters 2010, 12, 5438–5441.
Shoulders, M.D.; Kamer, K.J.; Raines, R.T. “Origin of the Stability Conferred upon Collagen by Fluorination” Bioorganic and Medicinal Chemistry Letters 2009, 19, 3859–3862.
Shoulders, M.D.; Raines, R.T. “Collagen Structure and Stability” Annual Review of Biochemistry 2009, 78, 929–958.
Shoulders, M.D.; Guzei, I.A.; Raines, R.T. “4-Chloroprolines: Synthesis, Conformational Analysis, and Effect on the Collagen Triple Helix” Biopolymers 2008, 89, 443–454.
Shoulders, M.D.; Hodges, J.A.; Raines, R.T. “Reciprocity of Steric and Stereoelectronic Effects in the Collagen Triple Helix” Journal of the American Chemical Society 2006, 128, 8112–8113.
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