A study in Science introduces a new way to solubilize membrane proteins without detergents using computationally designed “WRAPs” (Water-Soluble RFdiffused Amphipathic Proteins), making some of biology’s most challenging proteins easier to study.
Publications
Published in: Science
Authors: Ljubica Mihaljevic, David Kim, Pooja Bandawane, Helen Eisenach, Andrew Borst, Alexis Courbet, Connor Weidle, Kenneth Carr, Everton Bettin, Qiushi Liu, Aldo Trejos, Sagardip Majumder, Surabhi Kokane, Alexander Stevens, Edin Muratspahić, Thimas Schlichthaerle, Marc Expòsit, Xinting Li, Mila Lamb, Analisa Nicole Azcárraga Murray, Rashmi Ravichandran, Elizabeth Williams, Shuyuan Hu, Lynda Stuart, Linda Grillová, Nicholas Thomson, Michael Landreh, Pengxiang Chang, Lorenzo Giacani, Melissa Caimano, Kelly Hawley, Neil King, and David Baker
Embedded in the cell membrane at the boundary between the inside and outside of cells, membrane proteins act as first responders, sensing signals, regulating which molecules go in and out of the cell, and enabling cells to quickly adapt to changes in their environment.
Built for life in the cell’s oily membrane, the membrane protein surface repels water, forcing scientists to use detergents to extract them—often a tedious, multi-step process that requires extensive optimization and can limit downstream applications.
Now, researchers at the Institute for Protein Design (IPD) at the University of Washington (UW) School of Medicine have developed a new solution: custom-designed proteins that wrap around membrane proteins, shielding their hydrophobic surfaces and allowing them to remain soluble and stable in water without detergents.
WRAPs are genetically fused to their membrane protein targets and purified directly from the soluble fraction, bypassing the membrane altogether without having to modify native sequence. The team showed that WRAPs solubilize a wide range of membrane proteins while preserving their native structure, validated by a high-resolution (2.95 Å) structure of a WRAPed Mycobacterial porin. This establishes, for the first time, that membrane protein structures can be determined in solution without detergents, using WRAPs.
“Membrane proteins are incredibly important but notoriously difficult to work with. WRAPs give us a way to keep them intact in water, which opens up many new possibilities for both research and therapeutic application.” —David Baker, PhD, senior author, 2024 Nobel laureate, and professor of biochemistry, Howard Hughes Medical Institute investigator, and director of the IPD at the UW School of Medicine.
Broad applications in medicine and biotechnology
WRAPs unlock broad applications across vaccines, diagnostics, and drug discovery by making membrane proteins experimentally accessible without compromising structural and functional features. A compelling example is the outer membrane proteins of Treponema pallidum, the bacterium that causes syphilis, which are prime antigens that have long resisted production and structural characterization. WRAPs changed that by delivering stable, soluble antigens that can be finally characterized and translated into vaccines and diagnostics.
For drug development, WRAPs provide membrane protein targets compatible with high-throughput screening and structural analysis of drug–target interactions.
“I’m excited to finally release our WRAP approach to the broader scientific community and to see how it accelerates discovery in the membrane protein field” —Ljubica Mihaljevic, PhD, lead author and postdoctoral researcher at the UW IPD.
This study received support from several sources. All funders are listed in the manuscript, which has been assigned DOI: 10.1126/science.adr3817