The Schmidt lab invents and applies protein engineering technologies to study fundamental functional principles of natural and artificial living systems at a cellular level.
We are seeking mechanistic explanations for how cells sense, integrate and exchange information, how pathologic changes in these processes relate to health and disease, and provide insights into new therapies.
Typical questions we ask are: What are the minimally required functional features of cellular components that regulate cellular homeostasis and signal transduction? How does their activity change during normal development? What are specific activity patterns associated with disease onset? What are potential ways to re-engineer cellular signaling systems for therapeutic purposes?
We answer these questions by inventing custom-made methods to observe, delineate and precisely control cellular physiology. Our approach employs techniques from multiple disciplines including optogenetics, electrophysiology, and rational protein design.
We collaborate extensively to apply our technologies to diverse problems in human health. For example, to recapitulate misregulation of specific ion channels and receptors in models of cardiovascular disorders, to reveal how specific cell types contribute to the different neural circuits that underlie cognition and behavior, and to establish clear correlations between specific changes in regulated cell signaling networks and molecular signature of tumors enabling tumor proliferation and migration.
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Selected Publications: PubMed Search
Coyote-Maestas, W.*, Nedrud, D.*, Okorafor S., He Y., and Schmidt D. (2019) Targeted insertional mutagenesis libraries for deep domain insertion profiling. Nucleic Acid Research. 1-15, doi: 10.1093/nar/gkz1110
Domain insertion permissibility-guided engineering of allostery in ion channels Coyote-Maestas W., He Y., Myers C.L., Schmidt D. (2019) Nature Communications 10:290, doi: 10.1038/s41467-018-08171-0
Combinatorial Assembly of Lumitoxins. Nedrud D., Schmidt D. (2018) Methods in Molecular Biology, doi: 10.1007/978-1-4939-7362-0_15
Schmidt D. & Cho, Y.K. (2014) Natural photoreceptors and their application to synthetic biology. Trends in Biotechnology, doi:10.1016/j.tibtech.2014.10.007
Schmidt D., Tillberg P.W., Chen F., Boyden E.S. (2013) A fully genetically encoded protein architecture for optical control of peptide ligand concentration. Nature Communications 4:3019, doi:10.1038/ncomms4019
Schmidt D., del Marmol J., Mackinnon R. (2012) Mechanistic basis for low threshold mechanosensitivity in voltage-dependent K+ channels. PNAS 109(26):10352-7
Schmidt D., Cross S.R., Mackinnon R. (2009) A Gating Model for the Archaeal Voltage-Dependent K+ Channel KvAP in DPhPC and POPE:POPG decane lipid bilayers. J Mol Biol 390(5):902-12
Schmidt D., Mackinnon R (2008). Voltage-dependent K+ channel gating and voltage sensor toxin sensitivity depend on the mechanical state of the lipid membrane. PNAS 105(49):19275-80
Schmidt D.*, Jiang Q.X.*, Mackinnon R. (2006). Phospholipids and the origin of cationic gating charges in voltage sensors. Nature 444(7120):775-9