Journal Article: Flow cytometric reporter assays provide robust functional analysis of signaling complexes
Muusse, Timothy W., Lee, Morris Y.L., Kim, Hyoyoung, Parat, Marie-Odile, Nanson, Jeffrey D., Kobe, Bostjan, Vajjhala, Parimala R. and Stacey, Katryn J. (2022). Flow cytometric reporter assays provide robust functional analysis of signaling complexes. Journal of Biological Chemistry, 298 (12) 102666, 102666. doi: 10.1016/j.jbc.2022.102666
Journal Article: Cyclic ADP ribose isomers: Production, chemical structures, and immune signaling
Manik, Mohammad K., Shi, Yun, Li, Sulin, Zaydman, Mark A., Damaraju, Neha, Eastman, Samuel, Smith, Thomas G., Gu, Weixi, Masic, Veronika, Mosaiab, Tamim, Weagley, James S., Hancock, Steven J., Vasquez, Eduardo, Hartley-Tassell, Lauren, Kargios, Nestoras, Maruta, Natsumi, Lim, Bryan Y. J., Burdett, Hayden, Landsberg, Michael J., Schembri, Mark A., Prokes, Ivan, Song, Lijiang, Grant, Murray, DiAntonio, Aaron, Nanson, Jeffrey D., Guo, Ming, Milbrandt, Jeffrey, Ve, Thomas and Kobe, Bostjan (2022). Cyclic ADP ribose isomers: Production, chemical structures, and immune signaling. Science, 377 (6614) eadc8969, eadc8969-+. doi: 10.1126/science.adc8969
Journal Article: Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules
Shi, Yun, Kerry, Philip S., Nanson, Jeffrey D., Bosanac, Todd, Sasaki, Yo, Krauss, Raul, Saikot, Forhad K., Adams, Sarah E., Mosaiab, Tamim, Masic, Veronika, Mao, Xianrong, Rose, Faith, Vasquez, Eduardo, Furrer, Marieke, Cunnea, Katie, Brearley, Andrew, Gu, Weixi, Luo, Zhenyao, Brillault, Lou, Landsberg, Michael J., DiAntonio, Aaron, Kobe, Bostjan, Milbrandt, Jeffrey, Hughes, Robert O. and Ve, Thomas (2022). Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules. Molecular Cell, 82 (9), 1643-1659.e10. doi: 10.1016/j.molcel.2022.03.007
Structure and function of mammalian TIR domain-containing proteins
Doctor Philosophy
Structure and Function of SARM1
Doctor Philosophy
Structural biology of TIR domain-containing proteins
Doctor Philosophy
Characterisation of higher-order assembly formation in Toll-like receptor (TLR) signaling pathways
Toll-like receptors (TLRs) detect pathogen- and endogenous danger-associated molecules (PAMPs/DAMPs) and initiate innate immune responses that lead to the production of pro-inflammatory cytokines. TLR signal transduction occurs through the cytoplasmic Toll/interleukin-1 receptor (TIR) domain of the receptor. Upon activation of TLRs, the TIR domain of the receptor recruits TIR-containing adaptor proteins. Recruitment of these adaptors via TIR domain:TIR domain interactions orchestrates downstream signaling pathways, leading to induction of the pro-inflammatory genes.
Recent efforts directed at elucidating the structural basis of TIR domain self-association suggest signaling by TLR and adaptor protein TIR domains occurs through a higher-order assembly mechanism termed signaling by co-operative assembly formation (SCAF) [1]. The TIR domain of adapter protein MAL has been shown to spontaneously form filaments (helical assemblies) in vitro, form assemblies with other TIR domains, and induce the formation of large MyD88 (myddosome-like) assemblies [2].
This project involves spectroscopy, electron microscopy, and crystallography to determine the structure of TLR signaling assemblies, and investigate the molecular mechanisms involved in the assembly formation and downstream signaling.
References [1] Nimma, S,. et al. (2017). “Towards the structure of the TIR-domain signalosome”. Current Opinion in Structural Biology, 43: 122-130. doi:10.1016/j.sbi.2016.12.014 [2] Ve, T,. et al. (2017). “Structural basis of TIR-domain-assembly formation in MAL- and MyD88-dependent TLR4 signaling”. Nature Structural and Molecular Biology, 24 9: 743-751. doi:10.1038/nsmb.3444
Flow cytometric reporter assays provide robust functional analysis of signaling complexes
Muusse, Timothy W., Lee, Morris Y.L., Kim, Hyoyoung, Parat, Marie-Odile, Nanson, Jeffrey D., Kobe, Bostjan, Vajjhala, Parimala R. and Stacey, Katryn J. (2022). Flow cytometric reporter assays provide robust functional analysis of signaling complexes. Journal of Biological Chemistry, 298 (12) 102666, 102666. doi: 10.1016/j.jbc.2022.102666
Cyclic ADP ribose isomers: Production, chemical structures, and immune signaling
Manik, Mohammad K., Shi, Yun, Li, Sulin, Zaydman, Mark A., Damaraju, Neha, Eastman, Samuel, Smith, Thomas G., Gu, Weixi, Masic, Veronika, Mosaiab, Tamim, Weagley, James S., Hancock, Steven J., Vasquez, Eduardo, Hartley-Tassell, Lauren, Kargios, Nestoras, Maruta, Natsumi, Lim, Bryan Y. J., Burdett, Hayden, Landsberg, Michael J., Schembri, Mark A., Prokes, Ivan, Song, Lijiang, Grant, Murray, DiAntonio, Aaron, Nanson, Jeffrey D., Guo, Ming, Milbrandt, Jeffrey, Ve, Thomas and Kobe, Bostjan (2022). Cyclic ADP ribose isomers: Production, chemical structures, and immune signaling. Science, 377 (6614) eadc8969, eadc8969-+. doi: 10.1126/science.adc8969
Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules
Shi, Yun, Kerry, Philip S., Nanson, Jeffrey D., Bosanac, Todd, Sasaki, Yo, Krauss, Raul, Saikot, Forhad K., Adams, Sarah E., Mosaiab, Tamim, Masic, Veronika, Mao, Xianrong, Rose, Faith, Vasquez, Eduardo, Furrer, Marieke, Cunnea, Katie, Brearley, Andrew, Gu, Weixi, Luo, Zhenyao, Brillault, Lou, Landsberg, Michael J., DiAntonio, Aaron, Kobe, Bostjan, Milbrandt, Jeffrey, Hughes, Robert O. and Ve, Thomas (2022). Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules. Molecular Cell, 82 (9), 1643-1659.e10. doi: 10.1016/j.molcel.2022.03.007
Liu, Liping, Lucas, Richard M., Nanson, Jeffrey D., Li, Yan, Whitfield, Jason, Curson, James E. B., Tuladhar, Neeraj, Alexandrov, Kirill, Mobli, Mehdi, Sweet, Matthew J., Kobe, Bostjan, Stow, Jennifer and Luo, Lin (2022). The transmembrane adaptor SCIMP recruits tyrosine kinase Syk to phosphorylate Toll-like receptors to mediate selective inflammatory outputs. Journal of Biological Chemistry, 298 (5) 101857, 101857. doi: 10.1016/j.jbc.2022.101857
Nimma, Surekha, Gu, Weixi, Manik, Mohammad K., Ve, Thomas, Nanson, Jeffrey D. and Kobe, Bostjan (2022). Crystal structure of the Toll/interleukin‐1 receptor (TIR) domain of IL‐1R10 provides structural insights into TIR domain signaling. FEBS Letters, 596 (7), 886-897. doi: 10.1002/1873-3468.14288
Structural evolution of TIR-domain signalosomes
Nimma, Surekha, Gu, Weixi, Maruta, Natsumi, Li, Yan, Pan, Mengqi, Saikot, Forhad Karim, Lim, Bryan Y. J., McGuinness, Helen Ying, Zaoti, Zannati Ferdous, Li, Sulin, Desa, Sneha, Manik, Mohammad Kawsar, Nanson, Jeffrey D. and Kobe, Bostjan (2021). Structural evolution of TIR-domain signalosomes. Frontiers in Immunology, 12 784484, 1-10. doi: 10.3389/fimmu.2021.784484
Gu, Weixi, Luo, Zhenyao, Vonrhein, Clemens, Jia, Xinying, Ve, Thomas, Nanson, Jeffrey D. and Kobe, Bostjan (2021). Crystal structure determination of the armadillo repeat domain of Drosophila SARM1 using MIRAS phasing. Acta Crystallographica. Section F: Structural Biology Communications, 77 (10), 364-373. doi: 10.1107/s2053230x21006786
Clabbers, Max T. B., Holmes, Susannah, Muusse, Timothy W., Vajjhala, Parimala R., Thygesen, Sara J., Malde, Alpeshkumar K., Hunter, Dominic J. B., Croll, Tristan I., Flueckiger, Leonie, Nanson, Jeffrey D., Rahaman, Md. Habibur, Aquila, Andrew, Hunter, Mark S., Liang, Mengning, Yoon, Chun Hong, Zhao, Jingjing, Zatsepin, Nadia A., Abbey, Brian, Sierecki, Emma, Gambin, Yann, Stacey, Katryn J., Darmanin, Connie, Kobe, Bostjan, Xu, Hongyi and Ve, Thomas (2021). MyD88 TIR domain higher-order assembly interactions revealed by microcrystal electron diffraction and serial femtosecond crystallography. Nature Communications, 12 (1) 2578, 1-14. doi: 10.1038/s41467-021-22590-6
SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration
Figley, Matthew D., Gu, Weixi, Nanson, Jeffrey D., Shi, Yun, Sasaki, Yo, Cunnea, Katie, Malde, Alpeshkumar K., Jia, Xinying, Luo, Zhenyao, Saikot, Forhad K., Mosaiab, Tamim, Masic, Veronika, Holt, Stephanie, Hartley-Tassell, Lauren, McGuinness, Helen Y., Manik, Mohammad K., Bosanac, Todd, Landsberg, Michael J., Kerry, Philip S., Mobli, Mehdi, Hughes, Robert O., Milbrandt, Jeffrey, Kobe, Bostjan, DiAntonio, Aaron and Ve, Thomas (2021). SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration. Neuron, 109 (7), 1-19. doi: 10.1016/j.neuron.2021.02.009
Structural basis for nuclear import selectivity of pioneer transcription factor SOX2
Jagga, Bikshapathi, Edwards, Megan, Pagin, Miriam, Wagstaff, Kylie M., Aragão, David, Roman, Noelia, Nanson, Jeffrey D., Raidal, Shane R., Dominado, Nicole, Stewart, Murray, Jans, David A., Hime, Gary R., Nicolis, Silvia K., Basler, Christopher F. and Forwood, Jade K. (2021). Structural basis for nuclear import selectivity of pioneer transcription factor SOX2. Nature Communications, 12 (1) 28, 1-11. doi: 10.1038/s41467-020-20194-0
Structure, function, and regulation of thioesterases
Swarbrick, Crystall M.D., Nanson, Jeffrey D., Patterson, Edward I. and Forwood, Jade K. (2020). Structure, function, and regulation of thioesterases. Progress in Lipid Research, 79 101036, 101036. doi: 10.1016/j.plipres.2020.101036
Patterson, Edward I., Nanson, Jeffrey D., Abendroth, Jan, Bryan, Cassie, Sankaran, Banumathi, Myler, Peter J. and Forwood, Jade K. (2020). Structural characterisation of β-Ketoacyl ACP synthase I bound to platencin and fragment screening molecules at two substrate binding sites. Proteins: Structure, Function, and Bioinformatics, 88 (1) prot.25765, 47-56. doi: 10.1002/prot.25765
Cross, Emily M., Aragão, David, Smith, Kate M., Shaw, Karli I., Nanson, Jeffrey D., Raidal, Shane R. and Forwood, Jade K. (2019). Structural characterization of a short-chain dehydrogenase/reductase from multi-drug resistant Acinetobacter baumannii. Biochemical and Biophysical Research Communications, 518 (3), 465-471. doi: 10.1016/j.bbrc.2019.08.056
NAD+ cleavage activity by animal and plant TIR domains in cell death pathways
Horsefield, Shane, Burdett, Hayden, Zhang, Xiaoxiao, Manik, Mohammad K., Shi, Yun, Chen, Jian, Qi, Tiancong, Gilley, Jonathan, Lai, Jhih-Siang, Rank, Maxwell X., Casey, Lachlan W., Gu, Weixi, Ericsson, Daniel J., Foley, Gabriel, Hughes, Robert O., Bosanac, Todd, von Itzstein, Mark, Rathjen, John P., Nanson, Jeffrey D., Boden, Mikael, Dry, Ian B., Williams, Simon J., Staskawicz, Brian J., Coleman, Michael P., Ve, Thomas, Dodds, Peter N. and Kobe, Bostjan (2019). NAD+ cleavage activity by animal and plant TIR domains in cell death pathways. Science, 365 (6455), 793-799. doi: 10.1126/science.aax1911
Death, TIR, and RHIM: Self-assembling domains involved in innate immunity and cell-death signaling
Nanson, Jeffrey D., Kobe, Bostjan and Ve, Thomas (2019). Death, TIR, and RHIM: Self-assembling domains involved in innate immunity and cell-death signaling. Journal of Leukocyte Biology, 105 (2), 363-375. doi: 10.1002/JLB.MR0318-123R
Nanson, Jeffrey D., Rahaman, Habibur, Ve, Thomas and Kobe, Bostjan (2018). Regulation of signaling by cooperative assembly formation in mammalian innate immunity signalosomes by molecular mimics. Seminars in Cell and Developmental Biology, 99, 96-114. doi: 10.1016/j.semcdb.2018.05.002
Soares Da Costa, Tatiana P., Nanson, Jeffrey D. and Forwood, Jade K. (2017). Structural characterisation of the fatty acid biosynthesis enzyme FabF from the pathogen Listeria monocytogenes. Scientific Reports, 7 (1) 39277, 39277. doi: 10.1038/srep39277
Nanson, Jeffrey D. and Forwood, Jade K. (2015). Structural characterisation of FabG from yersinia pestis, a key component of bacterial fatty acid synthesis. PloS One, 10 (11) e0141543, e0141543. doi: 10.1371/journal.pone.0141543
Nanson, Jeffrey D., Himiari, Zainab, Swarbrick, Crystall M. D. and Forwood, Jade K. (2015). Structural characterisation of the Beta-Ketoacyl-Acyl carrier protein synthases, FabF and FabH, of Yersinia pestis. Scientific Reports, 5 (1) 14797. doi: 10.1038/srep14797
Swarbrick, Crystall M. D., Roman, Noelia, Cowieson, Nathan, Patterson, Edward I., Nanson, Jeffrey, Siponen, Marina I., Berglund, Helena, Lehtio, Lari and Forwood, Jade K. (2014). Structural basis for regulation of the human acetyl-CoA thioesterase 12 and interactions with the steroidogenic acute regulatory protein-related lipid transfer (START) domain. Journal of Biological Chemistry, 289 (35), 24263-24274. doi: 10.1074/jbc.M114.589408
Crystallization and preliminary X-ray diffraction analysis of FabG from Yersinia pestis
Nanson, Jeffrey David and Forwood, Jade Kenneth (2014). Crystallization and preliminary X-ray diffraction analysis of FabG from Yersinia pestis. Acta Crystallographica Section F: Structural Biology and Crystallization Communications, 70 (1), 101-104. doi: 10.1107/S2053230X13033402
Structure and function of mammalian TIR domain-containing proteins
Doctor Philosophy — Associate Advisor
Other advisors:
Structure and Function of SARM1
Doctor Philosophy — Associate Advisor
Other advisors:
Structural biology of TIR domain-containing proteins
Doctor Philosophy — Associate Advisor
Other advisors:
Structure and function of bacterial TIR domain-containing proteins
Doctor Philosophy — Associate Advisor
Other advisors:
Molecular mechanisms of signalling by plant immune receptors
Doctor Philosophy — Associate Advisor
Other advisors:
Structural basis of signalling by Toll-like receptor adaptors TRAM and TRIF
Doctor Philosophy — Associate Advisor
Other advisors:
Structural studies of proteins involved in innate immunity and cell death
Doctor Philosophy — Associate Advisor
Other advisors:
Understanding the molecular mechanism of signaling by cooperative assembly formation in Toll-like receptor pathways
Doctor Philosophy — Associate Advisor
Other advisors:
Structural and biochemical basis of NAD+ nucleosidase activity of TIR domain- containing proteins.
(2021) Doctor Philosophy — Associate Advisor
Other advisors:
Note for students: The possible research projects listed on this page may not be comprehensive or up to date. Always feel free to contact the staff for more information, and also with your own research ideas.
Characterisation of higher-order assembly formation in Toll-like receptor (TLR) signaling pathways
Toll-like receptors (TLRs) detect pathogen- and endogenous danger-associated molecules (PAMPs/DAMPs) and initiate innate immune responses that lead to the production of pro-inflammatory cytokines. TLR signal transduction occurs through the cytoplasmic Toll/interleukin-1 receptor (TIR) domain of the receptor. Upon activation of TLRs, the TIR domain of the receptor recruits TIR-containing adaptor proteins. Recruitment of these adaptors via TIR domain:TIR domain interactions orchestrates downstream signaling pathways, leading to induction of the pro-inflammatory genes.
Recent efforts directed at elucidating the structural basis of TIR domain self-association suggest signaling by TLR and adaptor protein TIR domains occurs through a higher-order assembly mechanism termed signaling by co-operative assembly formation (SCAF) [1]. The TIR domain of adapter protein MAL has been shown to spontaneously form filaments (helical assemblies) in vitro, form assemblies with other TIR domains, and induce the formation of large MyD88 (myddosome-like) assemblies [2].
This project involves spectroscopy, electron microscopy, and crystallography to determine the structure of TLR signaling assemblies, and investigate the molecular mechanisms involved in the assembly formation and downstream signaling.
References [1] Nimma, S,. et al. (2017). “Towards the structure of the TIR-domain signalosome”. Current Opinion in Structural Biology, 43: 122-130. doi:10.1016/j.sbi.2016.12.014 [2] Ve, T,. et al. (2017). “Structural basis of TIR-domain-assembly formation in MAL- and MyD88-dependent TLR4 signaling”. Nature Structural and Molecular Biology, 24 9: 743-751. doi:10.1038/nsmb.3444