Minglei Zhao

Associate Professor
Research Summary
As a structural biology lab, we are interested in understanding the mechanism of molecular machines and their roles in human diseases. Currently we focus on two systems, p97 / ubiquitination system, and vault. p97 is a central hub in cellular protein homeostasis. It is involved in several neurodegenerative diseases, and is also a cancer drug target. We want to gain insights into the molecular architectures of p97 in complex with various cofactor proteins and poly-ubiquitinated substrates. We are investigating the specificity of p97 towards ubiquitin chains with various topologies. Our findings will elucidate the molecular mechanism of human p97. Vault is the largest ribonuclear protein in many eukaryotes including human. It is a membraneless organelle. Despite the fact that vault has been studied for thirty years, its function remains elusive. Overexpression of major vault protein (MVP) correlates with drug resistance in cancer cells. However, the mechanism is completely unknown at the molecular level. We are investigating the structures of vault components and using proteomic and imaging techniques to address the molecular function of vault. There are two major techniques used in the lab: X-ray crystallography and cryo-electron microscopy.
AAA+ ATPase, p97, Ubiquitination, Vault RNP Particle
  • Stanford University and Howard Hughes Medical Institute, California, USA, Biophysics and Structural Biology 12/2016
  • University of California Los Angeles, California, USA, Ph.D. Molecular Biology 12/2011
  • Fudan University, Shanghai, China, B.S. Biological Sciences 06/2005
Biosciences Graduate Program Association
  1. A novel membrane complex is required for docking and regulated exocytosis of lysosome-related organelles in Tetrahymena thermophila. PLoS Genet. 2022 05; 18(5):e1010194. View in: PubMed

  2. Structural basis for the mechanisms of human presequence protease conformational switch and substrate recognition. Nat Commun. 2022 04 05; 13(1):1833. View in: PubMed

  3. Structural insights into Ubr1-mediated N-degron polyubiquitination. Nature. 2021 12; 600(7888):334-338. View in: PubMed

  4. Mechanistic insight into substrate processing and allosteric inhibition of human p97. Nat Struct Mol Biol. 2021 07; 28(7):614-625. View in: PubMed

  5. K29-linked ubiquitin signaling regulates proteotoxic stress response and cell cycle. Nat Chem Biol. 2021 08; 17(8):896-905. View in: PubMed

  6. Seesaw conformations of Npl4 in the human p97 complex and the inhibitory mechanism of a disulfiram derivative. Nat Commun. 2021 01 05; 12(1):121. View in: PubMed

  7. Structural analysis of Mycobacterium tuberculosis M13 metalloprotease Zmp1 open states. Structure. 2021 07 01; 29(7):709-720.e3. View in: PubMed

  8. Alternative splicing controls teneurin-latrophilin interaction and synapse specificity by a shape-shifting mechanism. Nat Commun. 2020 05 01; 11(1):2140. View in: PubMed

  9. Structural basis for adhesion G protein-coupled receptor Gpr126 function. Nat Commun. 2020 01 10; 11(1):194. View in: PubMed

  10. Structural principles of SNARE complex recognition by the AAA+ protein NSF. Elife. 2018 09 10; 7. View in: PubMed

  11. Stem cell heterogeneity drives the parasitic life cycle of Schistosoma mansoni. Elife. 2018 07 10; 7. View in: PubMed

  12. NSF-mediated disassembly of on- and off-pathway SNARE complexes and inhibition by complexin. Elife. 2018 07 09; 7. View in: PubMed

  13. Atomic structures of FUS LC domain segments reveal bases for reversible amyloid fibril formation. Nat Struct Mol Biol. 2018 04; 25(4):341-346. View in: PubMed

  14. The primed SNARE-complexin-synaptotagmin complex for neuronal exocytosis. Nature. 2017 08 24; 548(7668):420-425. View in: PubMed

  15. Molecular Mechanisms of Synaptic Vesicle Priming by Munc13 and Munc18. Neuron. 2017 Aug 02; 95(3):591-607.e10. View in: PubMed

  16. Advances in X-ray free electron laser (XFEL) diffraction data processing applied to the crystal structure of the synaptotagmin-1 / SNARE complex. Elife. 2016 10 12; 5. View in: PubMed

  17. N-terminal domain of complexin independently activates calcium-triggered fusion. Proc Natl Acad Sci U S A. 2016 08 09; 113(32):E4698-707. View in: PubMed

  18. Complexin induces a conformational change at the membrane-proximal C-terminal end of the SNARE complex. Elife. 2016 06 02; 5. View in: PubMed

  19. Recent Advances in Deciphering the Structure and Molecular Mechanism of the AAA+ ATPase N-Ethylmaleimide-Sensitive Factor (NSF). J Mol Biol. 2016 05 08; 428(9 Pt B):1912-26. View in: PubMed