Native Cell Membrane Nanoparticles System

NIH Pandemic-Era Grants

Pandemic Era Grants

2022

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Principal Investigator: Youzhong  Guo
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
Fiscal Year: 2022
Award: $382,600
Funding agency: National Institute of General Medical Sciences

SUMMARY
Membrane proteins play crucial roles in living organisms. Protein-lipid interactions are crucial for the
structural and functional integrity of membrane proteins. High-resolution of membrane protein structures
are in high-demand for both understanding their biology and structure-based drug discovery. It is often need
to extract membrane proteins from cell membranes for biochemical and biophysical study. Currently
detergents are predominantly used for membrane protein extraction. Detergents have significant drawbacks
in that they destroy lipid bilayer and remove important lipid molecules from membrane proteins. We are
developing a detergent-free native cell membrane nanoparticles system for membrane protein research. The
native cell membrane nanoparticles system is composed of three components: 1) Membrane active
polymers. 2) Protocols for preparation of native cell membrane nanoparticles. 3) Single-particles cryo-EM
analysis of the native cell membrane nanoparticles. We propose to develop a system that can be generally
applicable to both prokaryotic and eukaryotic membrane proteins. Specific Aim 1 focuses on construction
of membrane active polymer library and develop protocols for preparation of native cell membrane
nanoparticles using our selected model membrane proteins. We have developed four prototype membrane
active polymers, with the similar strategies we plan to expand the membrane active polymers using both
commercially available styrene maleic anhydride copolymers and polymers synthesized in laboratories.
Specific Ami 2 focuses on developing protocols for high-resolution structure determination of selected
prokaryotic model membrane proteins. Specific Aim 3 focuses on developing protocols for high-resolution
structures of selected eukaryotic model membrane proteins. The proposed research is significant because it
provides a revolutionary detergent-free approach for study membrane proteins in their local lipid
environment. As we have demonstrated in our preliminary data, we found the structural information of
protein-lipid interaction for membrane proteins is crucial for understanding the structure and function of
membrane proteins. This system might transform the membrane protein research field and have a great
impact for membrane protein structure based drug discovery and development.

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