Our lab is interested in how cell surface receptors convert signals from extracellular stimuli like mechanical force into a biological response, as dysregulation in a cell’s force-sensing ability can lead to disease. We use X-ray crystallography and other biophysical methods to ask what “mechanosensors” look like in order to understand the range of structures nature uses to sense forces of different magnitudes and in different contexts, and hopefully identify potentially novel therapeutic targets. We also use and develop single molecule and cell-based assays based on magnetic tweezers to apply forces to mechanosensors to probe how mechanosensors are converted from an “off” to “on” state. We measure both magnitudes of forces to effect a biological response and are developing methods to probe the corresponding structural changes that occur. Finally, we are developing general signaling assays to help us map mechanosensor domains, understand differences between on and off states, and search for new potential mechanosensors.
Gordon WR, Miles LJ, He L, Huang J, Tiyanont K, McArthur DG, Zimmerman B, Aster JC, Perrimon N, Loparo JJ, and Blacklow SC. (2014) Mechanical Allostery: Proteolytic Activation of Notch Induced by Intercellular Delivery of Force, submitted
Gordon WR, Aster JC (2014). Application and evaluation of anti-notch antibodies to modulate notch signaling. Methods Mol Biol.1187:323-33.
Gordon WR, Bang D, Hoff WD, Kent SB (2013). Total chemical synthesis of fully functional Photoactive Yellow Protein.Bioorg Med Chem. 21(12):3436-42.
Aste-Amézaga M, Zhang N, Lineberger JE, Arnold BA, Toner TJ, Gu M, Huang L, Vitelli S, Vo KT, Haytko P, Zhao JZ, Baleydier F, L'Heureux S, Wang H, Gordon WR, Thoryk E, Andrawes MB, Tiyanont K, Stegmaier K, Roti G, Ross KN, Franlin LL, Wang H, Wang F, Chastain M, Bett AJ, Audoly LP, Aster JC, Blacklow SC, Huber HE. Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors. PLoS One. 5(2):e9094.
Gordon WR, Vardar-Ulu D, L'Heureux S, Ashworth T, Malecki MJ, Sanchez-Irizarry C, McArthur DG, Histen G, Mitchell JL, Aster JC, Blacklow SC. (2009) Effects of S1 cleavage on the structure, surface export, and signaling activity of human Notch1 and Notch2. PLoS One. 4(8):e6613.
Gordon WR, Roy M, Vardar-Ulu D, Garfinkel M, Mansour MR, Aster JC, Blacklow SC.(2009) Structure of the Notch1-negative regulatory region: implications for normal activation and pathogenic signaling in T-ALL. Blood.113(18):4381-90.
Gordon WR, Arnett KL, Blacklow SC (2008).The molecular logic of Notch signaling--a structural and biochemical perspective.J Cell Sci. 121(Pt 19):3109-19.
Li K, Li Y, Wu W, Gordon WR, Chang DW, Lu M, Scoggin S, Fu T, Vien L, Histen G, Zheng J, Martin-Hollister R, Duensing T, Singh S, Blacklow SC, Yao Z, Aster JC, Zhou BB (2008). Modulation of Notch signaling by antibodies specific for the extracellular negative regulatory region of NOTCH3. J Biol Chem. 283(12):8046-54.
Gordon WR*, Vardar-Ulu D*, Histen G, Sanchez-Irizarry C, Aster JC, Blacklow SC (2007). Structural basis for autoinhibition of Notch.Nat Struct Mol Biol. 14(4):295-300.