Professional Education


  • Bachelor of Science, Nankai University (2006)
  • Doctor of Philosophy, Baylor College Of Medicine (2019)
  • Ph.D, Baylor College of Medicine

Stanford Advisors


  • Wah Chiu, Postdoctoral Faculty Sponsor

All Publications


  • The Chaperonin TRiC/CCT Associates with Prefoldin through a Conserved Electrostatic Interface Essential for Cellular Proteostasis CELL Gestaut, D., Roh, S., Ma, B., Pintilie, G., Joachimiak, L. A., Leitner, A., Walzthoeni, T., Aebersold, R., Chiu, W., Frydman, J. 2019; 177 (3): 751-+
  • Control of the structural landscape and neuronal proteotoxicity of mutant Huntingtin by domains flanking the polyQ tract ELIFE Shen, K., Calamini, B., Fauerbach, J. A., Ma, B., Shahmoradian, S. H., Lachapei, I. L., Chiu, W., Lo, D. C., Frydman, J. 2016; 5

    Abstract

    Many neurodegenerative diseases are linked to amyloid aggregation. In Huntington's disease (HD), neurotoxicity correlates with an increased aggregation propensity of a polyglutamine (polyQ) expansion in exon 1 of mutant huntingtin protein (mHtt). Here we establish how the domains flanking the polyQ tract shape the mHtt conformational landscape in vitro and in neurons. In vitro, the flanking domains have opposing effects on the conformation and stabilities of oligomers and amyloid fibrils. The N-terminal N17 promotes amyloid fibril formation, while the C-terminal Proline Rich Domain destabilizes fibrils and enhances oligomer formation. However, in neurons both domains act synergistically to engage protective chaperone and degradation pathways promoting mHtt proteostasis. Surprisingly, when proteotoxicity was assessed in rat corticostriatal brain slices, either flanking region alone sufficed to generate a neurotoxic conformation, while the polyQ tract alone exhibited minimal toxicity. Linking mHtt structural properties to its neuronal proteostasis should inform new strategies for neuroprotection in polyQ-expansion diseases.

    View details for DOI 10.7554/eLife.18065

    View details for Web of Science ID 000390025200001

    View details for PubMedCentralID PMC5135392

  • TRiC's tricks inhibit huntingtin aggregation ELIFE Shahmoradian, S. H., Galaz-Montoya, J. G., Schmid, M. F., Cong, Y., Ma, B., Spiess, C., Frydman, J., Ludtke, S. J., Chiu, W. 2013; 2

    Abstract

    In Huntington's disease, a mutated version of the huntingtin protein leads to cell death. Mutant huntingtin is known to aggregate, a process that can be inhibited by the eukaryotic chaperonin TRiC (TCP1-ring complex) in vitro and in vivo. A structural understanding of the genesis of aggregates and their modulation by cellular chaperones could facilitate the development of therapies but has been hindered by the heterogeneity of amyloid aggregates. Using cryo-electron microscopy (cryoEM) and single particle cryo-electron tomography (SPT) we characterize the growth of fibrillar aggregates of mutant huntingtin exon 1 containing an expanded polyglutamine tract with 51 residues (mhttQ51), and resolve 3-D structures of the chaperonin TRiC interacting with mhttQ51. We find that TRiC caps mhttQ51 fibril tips via the apical domains of its subunits, and also encapsulates smaller mhtt oligomers within its chamber. These two complementary mechanisms provide a structural description for TRiC's inhibition of mhttQ51 aggregation in vitro. DOI:http://dx.doi.org/10.7554/eLife.00710.001.

    View details for DOI 10.7554/eLife.00710

    View details for Web of Science ID 000328620500004

    View details for PubMedID 23853712

    View details for PubMedCentralID PMC3707056

  • The Molecular Architecture of the Eukaryotic Chaperonin TRiC/CCT STRUCTURE Leitner, A., Joachimiak, L. A., Bracher, A., Moenkemeyer, L., Walzthoeni, T., Chen, B., Pechmann, S., Holmes, S., Cong, Y., Ma, B., Ludtke, S., Chiu, W., Hartl, F. U., Aebersold, R., Frydman, J. 2012; 20 (5): 814-825

    Abstract

    TRiC/CCT is a highly conserved and essential chaperonin that uses ATP cycling to facilitate folding of approximately 10% of the eukaryotic proteome. This 1 MDa hetero-oligomeric complex consists of two stacked rings of eight paralogous subunits each. Previously proposed TRiC models differ substantially in their subunit arrangements and ring register. Here, we integrate chemical crosslinking, mass spectrometry, and combinatorial modeling to reveal the definitive subunit arrangement of TRiC. In vivo disulfide mapping provided additional validation for the crosslinking-derived arrangement as the definitive TRiC topology. This subunit arrangement allowed the refinement of a structural model using existing X-ray diffraction data. The structure described here explains all available crosslink experiments, provides a rationale for previously unexplained structural features, and reveals a surprising asymmetry of charges within the chaperonin folding chamber.

    View details for DOI 10.1016/j.str.2012.03.007

    View details for Web of Science ID 000304214400008

    View details for PubMedID 22503819

    View details for PubMedCentralID PMC3350567

  • Symmetry-free cryo-EM structures of the chaperonin TRiC along its ATPase-driven conformational cycle EMBO JOURNAL Cong, Y., Schroeder, G. F., Meyer, A. S., Jakana, J., Ma, B., Dougherty, M. T., Schmid, M. F., Reissmann, S., Levitt, M., Ludtke, S. L., Frydman, J., Chiu, W. 2012; 31 (3): 720-730

    Abstract

    The eukaryotic group II chaperonin TRiC/CCT is a 16-subunit complex with eight distinct but similar subunits arranged in two stacked rings. Substrate folding inside the central chamber is triggered by ATP hydrolysis. We present five cryo-EM structures of TRiC in apo and nucleotide-induced states without imposing symmetry during the 3D reconstruction. These structures reveal the intra- and inter-ring subunit interaction pattern changes during the ATPase cycle. In the apo state, the subunit arrangement in each ring is highly asymmetric, whereas all nucleotide-containing states tend to be more symmetrical. We identify and structurally characterize an one-ring closed intermediate induced by ATP hydrolysis wherein the closed TRiC ring exhibits an observable chamber expansion. This likely represents the physiological substrate folding state. Our structural results suggest mechanisms for inter-ring-negative cooperativity, intra-ring-positive cooperativity, and protein-folding chamber closure of TRiC. Intriguingly, these mechanisms are different from other group I and II chaperonins despite their similar architecture.

    View details for DOI 10.1038/emboj.2011.366

    View details for Web of Science ID 000300871700019

    View details for PubMedID 22045336

    View details for PubMedCentralID PMC3273382

  • Cryo-EM Structure of a Group II Chaperonin in the Prehydrolysis ATP-Bound State Leading to Lid Closure STRUCTURE Zhang, J., Ma, B., DiMaio, F., Douglas, N. R., Joachimiak, L. A., Baker, D., Frydman, J., Levitt, M., Chiu, W. 2011; 19 (5): 633-639

    Abstract

    Chaperonins are large ATP-driven molecular machines that mediate cellular protein folding. Group II chaperonins use their "built-in lid" to close their central folding chamber. Here we report the structure of an archaeal group II chaperonin in its prehydrolysis ATP-bound state at subnanometer resolution using single particle cryo-electron microscopy (cryo-EM). Structural comparison of Mm-cpn in ATP-free, ATP-bound, and ATP-hydrolysis states reveals that ATP binding alone causes the chaperonin to close slightly with a ∼45° counterclockwise rotation of the apical domain. The subsequent ATP hydrolysis drives each subunit to rock toward the folding chamber and to close the lid completely. These motions are attributable to the local interactions of specific active site residues with the nucleotide, the tight couplings between the apical and intermediate domains within the subunit, and the aligned interactions between two subunits across the rings. This mechanism of structural changes in response to ATP is entirely different from those found in group I chaperonins.

    View details for DOI 10.1016/j.str.2011.03.005

    View details for Web of Science ID 000290815500006

    View details for PubMedID 21565698