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Yongli Zhang, PhD, MS

Professor of Cell Biology
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About

Titles

Professor of Cell Biology

Biography

Dr. Zhang obtained a bachelor's degree in applied physics and a master's degree in theoretical physics in China before he came to the US in 1997. He began to use pipettes as a graduate student in the Department of Molecular Biophysics and Biochemistry at Yale University and barely passed his qualifying exams. Fortunately, he seemed to do research well under the supervision of Prof. Donald M. Crothers and got a Ph. D. in 2003. His thesis work is related to the sequence-dependent DNA bending and flexibility. Dr. Zhang then became a postdoctoral fellow in Prof. Carlos Bustamante's lab at UC Berkeley. Using optical tweezers, he found that representative chromatin remodeling factors contain DNA translocases and first measured their translocation speed, processivity, and stall force.

Prof. Zhang has broad interests and skills in measuring the intra- and inter-molecular forces and the forces generated by molecular machines. He tries to use these measurements to better understand the working mechanisms and biological functions of macromolecules. With his collaborators, Prof. Zhang combines high-resolution optical tweezers with single-molecule fluorescence microscopy to simultaneously manipulate and visualize single molecules in real time. As a result, dynamic structures of proteins inaccessible by other experimental methods can be obtained. Prof. Zhang's primary interests are mechanical force in biology and folding dynamics of proteins involved in fundamental biological processes and human diseases, with a focus on SNARE proteins and their regulators essential for intracellular vesicle fusion.



Appointments

Education & Training

Postdoc fellow
University of California (2006)
PhD
Yale School of Medicine, Department of Molecular Biophysics and Biochemistry (2003)
MS
Chinese Academy of Sciences, Institute of Theoretical Physics (1997)

Research

Overview

We are focused on understanding the molecular mechanisms that underlie three important biological processes:

1. Regulated SNARE folding and assembly.

The membrane fusion machinery contains SNARE proteins, Sec1/Munc18 (SM) proteins, synaptotagmin, complexin, NSF, SNAP, and Munc13. Among these proteins, SNAREs are key players. They couple their dynamical assembly and disassembly to membrane fusion in a precisely controlled manner. Specifically, SNARE assembly generates force to draw two membranes into proximity and use their folding energy to lower the energy barrier of membrane fusion. SM proteins, synaptotagmin, and complexin regulate SNARE assembly and enable membrane fusion to occur at right time and location. After membrane fusion, NSF and SNAP disassemble the fully assembled SNARE complexes in an ATP-dependent manner, recycling SNAREs for next round of fusion. We plan to understand how the above mentioned proteins work together to control exocytosis and how malfunctions of the fusion machinery cause diseases.

Sudhof, T.C., and Rothman, J.E. (2009). Membrane fusion: Grappling with SNARE and SM proteins. Science 323, 474-477.

Y. Gao, S. Zorman, G. Gundersen, Z. Q. Xi, G. Sirinakis, J. E. Rothman*, Y. L. Zhang*, Single reconstituted neuronal SNARE complexes zipper in three distinct stages. Science 337: 1340-1343 (2012).

L. Ma, A. A. Rebane, G. Yang, Z. Xi, Y. Kang, Y. Gao, Y. L. Zhang, Munc18-1-regulated stage-wise SNARE assembly underlying synaptic exocytosis. eLIFE 4, e09580 (2015).

S. Zorman, A. A. Rebane, L. Ma, G. Yang, M. A. Molski, J. Coleman, F. Pincet, J. E. Rothman*, Y. L. Zhang*, Common intermediates and kinetics, but different energetics, in the assembly of SNARE proteins. eLIFE 3, e03348 (2014).

Y. L. Zhang, Energetics, kinetics, and pathway of SNARE folding and assembly revealed by optical tweezers, Protein Sci. 26, 1252-1265 (2017).

A. A. Rebane, B. Wang, L. Ma, H. Qu, J. Coleman, S. S. Krishnakumar, J. E. Rothman*, Y. L. Zhang*, Two disease-causing SNAP-25B mutations selectively impair SNARE C-terminal assembly. J. Mol. Biol. 430, 479 (2018).

J. Jiao, M. He, S. A. Port, R. W. Baker, Y. Xu, H. Qu, Y. Xiong, Y. Wang, H. Jin, T. J. Eisemann, F. M. Hughson*, Y. L. Zhang*, Munc18-1 catalyzes neuronal SNARE assembly by templating SNARE association. Elife 7, e41771 (2018).

* Co-corresponding authors.

2. Membrane protein folding, stability, and protein-membrane interactions.

Optical tweezers have been widely applied to study folding dynamics of soluble proteins, but not membrane proteins so far. We have been developing novel approaches to measure the folding energy and kinetics of membrane proteins using high-resolution optical tweezers. We are also interested in proteins that help membrane proteins get in and out membranes.


L. Ma, Y. Cai, Y. Li, J. Jiao, Z. Wu, B. O'Shaughnessy, P. De Camilli*, E. Karatekin*, Y. L. Zhang*, Single-molecule force spectroscopy of protein-membrane interactions. Elife 6, e30493 (2017)

3. Development of new single-molecule methods.

We have been developing new instruments or upgrading our machines by combining high-resolution optical tweezers, single-molecule fluorescence detection, and microfluidics to better study single proteins or protein complexes. We have been also developing new methods or algorithms to analyze data from single molecule experiments.

G. Sirinakis, Y. X. Ren, Y. Gao, Z. Q. Xi, Y. L. Zhang, Combined and versatile high-resolution optical tweezers and single-molecule fluorescence microscopy. Rev Sci Instrum. 83: 093708-(1-9) (2012).

Y. L. Zhang, J. Jiao, A. A. Rebane, Hidden Markov modeling with detailed balance and its application to single protein folding Biophys J 111, 2110 (2016).

A. A. Rebane, L. Ma, Y. L. Zhang, Structure-based derivation of protein folding intermediates and energies from optical tweezers. Biophys J 110, 441 (2016).


4. Molecular mechanism of the mechanosensitive ion channel NOMPC.

NOMPC is involved in mechanosensation of touch and hearing in flies. Unlike many mechanosensitive ion channels that sense membrane tension or force in the membrane, NOMPC has been proposed to sense force out of the membrane through a gating spring. In collaboration with groups of Yifan Cheng and Yuh-Nung Jan in UCSF, we have been investigating whether and how force modulates the ion conductance of NOMPC, using optical tweezers and fluorescence imaging.

  1. P. Jin, D. Bulkley, Y. M. Guo, W. Zhang, Z. H. Guo, W. Huynh, S. P. Wu, S. Meltzer, T. Cheng, L. Y. Jan, Y. N. Jan, Y. F. Cheng, Electron cryo-microscopy structure of the mechanotransduction channel NOMPC. Nature 547, 118 (2017).
  2. W. Zhang, L. E. Cheng, M. Kittelmann, J. F. Li, M. Petkovic, T. Cheng, P. Jin, Z. H. Guo, M. C. Gopfert, L. Y. Jan, Y. N. Jan, Ankyrin repeats convey force to gate the NOMPC mechanotransduction channel. Cell 162, 1391 (2015).

Medical Subject Headings (MeSH)

Chromatin Assembly and Disassembly; Exocytosis; Membrane Fusion; Munc18 Proteins; Optical Tweezers; Protein Folding; SNARE Proteins; Synaptic Transmission; Synaptotagmins

Research at a Glance

Yale Co-Authors

Frequent collaborators of Yongli Zhang's published research.

Publications

2024

2023

2022

2019

2018

2017

Academic Achievements & Community Involvement

  • honor

    Postdoctoral Fellowship

  • honor

    Sinsheimer Scholar

Get In Touch

Contacts

Academic Office Number
Secondary Academic Office Number
Lab Number
Mailing Address

Cell Biology

PO Box 208002, 333 Cedar Street

New Haven, CT 06520-8002

United States

Administrative Support

Locations

  • Sterling Hall of Medicine, I-Wing

    Academic Office

    333 Cedar Street, Ste Room E54A

    New Haven, CT 06510

    Appointments

    203.737.4536
  • Tweezers Lab

    Lab

    Sterling Hall of Medicine, I-Wing

    333 Cedar Street, Ste E90

    New Haven, CT 06510

    Appointments

    203.737.3356