420 Washington Avenue SE
Minneapolis, MN 55455
Scalable methods for high-throughput engineering of synthetic protein systems with applications in neural circuit mapping and gene therapy.
The Schmidt lab is engineering ion channels to endow them with user-controlled modulation. This would enable analysis of their roles in defined cell types, and in circuits containing those cell types neuromuscular tissue. We are developing the necessary experimental methods and analytical frameworks that will expand our understanding of ion channel gating and increase our ability to rationally engineer these functions. Another area is Adeno-Associated virus (AAV), which has emerged as a safe viral gene delivery vector but whose broad tropism limits cell-type specific infection. We address this shortcoming by engineering the viral capsid itself, so that we can replace broad tropism with precise, receptor-mediated targeting. The outcome is viral vectors that enable gene delivery to different cell types with minimal cross-talk or off-target effects.
Coyote-Maestas, W., Nedrud D., He Y., Schmidt D. (2022). “Determinants of trafficking, conduction, and disease within a K+ channel revealed through multiparametric deep mutational scanning.” Elife 11:e76903. doi: 10.7554/eLife.76903.
Coyote-Maestas W., Nedrud D., Suma A., He Y., Matreyek K.A., Fowler D., Carnevale V., Myers C.L., Schmidt D. (2021). “Probing Ion Channel Functional Architecture and Domain Recombination Compatibility by Massively Parallel Domain Insertion Profiling” Nature Communications. 2021 Dec 8;12(1):7114. doi: 10.1038/s41467-021-27342-0.
Nedrud, D., Coyote-Maestas W., Schmidt D. (2020). “A large-scale survey of pairwise epistasis reveals a mechanism for evolutionary expansion and specialization of PDZ domains”, bioRxiv https://doi.org/10.1101/2020.06.26.174375, PMCID: pending
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