Electron Tomography at Yale University


Structural basis of HIV viral entry 

Bacteriophage Infection

Bacteriophages direct the evolution of bacterial pathogenicity by imposing selection for resistance to infection and by horizontal gene transfer of host genes to new bacteria. Most phages utilize elaborate tail machines to eject their genome into a host cell. In addition, these highly sophisticated molecular machines are responsible for host-cell recognition, attachment, and cell envelope penetration. Understanding how tailed phages infect their bacterial hosts will not only provide insight into the evolution of bacterial pathogenicity, but will also illuminate basic biological problems such as molecular recognition, protein-protein, protein-DNA, protein-membrane interactions, and the transport of large macromolecules across cell membranes.

This project is supported by NIH/NIGMS.


Li Z, Li W, Lu M, Bess J Jr, Chao CW, Gorman J, Terry DS, Zhang B, Zhou T, Blanchard SC, Kwong PD, Lifson JD, Mothes W, Liu J: Subnanometer structures of HIV-1 envelope trimers on aldrithiol-2-inactivated virus particles.  Nat Struct Mol Biol. 2020 Aug;27(8):726-734. doi: 10.1038/s41594-020-0452-2. 

Wang C, Tu J, Liu J, Molineux IJ: Structural Dynamics of Bacteriophage P22 Infection Initiation Revealed by Cryo-electron Tomography, Nature Microbiology, 2019.

Tu J, Park T, Morado DR, Hughes KT, Molineux IJ, Liu J: Dual host specificity of phage SP6 is facilitated by tailspike rotation. Virology 2017, 507:206-215.

Farley M, Tu J, Kearns DB, Molineux IJ, Liu J: Ultrastructural analysis of bacteriophage Φ29 during infection of Bacillus subtilis. J Struct Biol 2016, S1047-8477(16)30167-8.

Hu B, Margolin W, Molineux IJ, and Liu J: Structural Remodeling of Bacteriophage T4 and Host Membranes During Infection Initiation. Proc Natl Acad Sci U S A 2015, 112(35):E4919-28.

Hu B, Margolin W, Molineux IJ, Liu J: The Bacteriophage T7 Virion Undergoes Extensive Structural Remodeling during infection, Science 339(6119):576-9, 2013.

Liu J, Chen CY, Shiomi D, Niki H, Margolin W: Visualization of bacteriophage P1 infection by cryo-electron tomography of tiny Escherichia coli. Virology 417(2):304-11, 2011.

Fu X, Walter MH, Paredes A, Morais MC, Liu J: The mechanism of DNA ejection in the Bacillus anthracis spore-binding phage 8a revealed by cryo-electron tomography. Virology 421(2):141-8, 2011.

Liu J, Wright ER, Winkler H: 3D visualization of HIV virions by cryoelectron tomography. Methods Enzymol 483:267-90, 2010.

Liu J, Bartesaghi A, Borgnia M, Sapiro G, Subramaniam S: Molecular architecture of native HIV-1 gp120 trimers, Nature 455:109-113, 2008.

The envelope glycoproteins (Envs) of HIV/SIV mediate binding to CD4 and co-receptors on target cells to initiate viral entry and infection. The Envs comprise the functional trimeric spikes on the surface of the viral membrane and is composed of glycoprotein (gp41) and a surface glycoprotein (gp120). Cryo-ET was utilized to determine the molecular architecture of native HIV-1 gp120 trimers on the envelope of virions [Liu et al. 2008 Nature]. For the first time, we were able to demonstrate the structural and conformational changes that occur upon the binding of the Env spikes of HIV to its host cell surface receptor (CD4) at 2.0nm resolution. The binding of Env to CD4 results in a major reorganization of the Env trimer and a close contact between the virus and target cell co-receptor, thus facilitating viral entry.