This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: To sense their environment and respond accordingly, cells enlist membrane proteins as communication hubs, receiving molecular messages from outside and triggering responses inside. One of these proteins is Toll-like receptor 4 (TLR4), an immune receptor that plays an essential role in protecting against infections.
But overactivity of TLR4 has been linked to inflammatory disorders like sepsis, arthritis and inflammatory bowel disease, making it an attractive target for therapies. Despite its appeal, TLR4 is difficult to manipulate precisely, and no FDA-approved drugs specifically block it. Now, in a new PNAS study, scientists at Scripps Research engineered a small synthetic protein that can bind to TLR4 within cell membranes and block subsequent inflammatory responses.
The findings advance understanding of what TLR4's membrane-embedded region does. Rather than a passive anchor, it's an active determinant of cross-membrane signaling—mechanistic insight that could guide the design of a new class of anti-inflammatory treatments. More broadly, the study outlines new computational tools that other researchers can use to target proteins within membranes.
"People assumed that the regions of TLR4 exposed outside and inside the cell were the main signaling drivers, but we showed that the membrane-spanning region is also critical for this function," says the study's first author, Colleen Maillie, a research project analyst at Scripps Research. The cell membrane is composed of two compact layers of oily molecules. This gives the membrane very different biochemical properties from the water-based environments found outside and within the cell, where the majority of proteins reside.
Many of the rules governing how proteins fold and function within these oily membranes are still unclear, which has made it challenging for researchers to design drugs that act there. But Maillie and a team of scientists in the labs of co-senior authors assistant professor Marco Mravic and professor Andrew Ward of Scripps Research were determined to develop a new method to better access and manipulate membrane proteins. For this study, they selected TLR4.
"TLR4 is a key sensor of bacteria that activates and mobilizes immune cells to fight infection," says Ward. "It may be activated by adjuvants in vaccines to improve immune responses or inhibited to suppress inflammation, making it both a sensor and a dial to tune innate immunity." Generally, when the exposed portion of TLR4 detects a bacterial molecule outside the cell, it triggers changes in the receptor that prompt it to form dimers, or pairs of two TLR4 proteins. These dimers then sometimes—but not always—switch on an inflammatory response in the cell.
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