Fleeting interactions between membrane sugar chains control cell division

Acting as an armor, a scaffold, and a communication platform in one, our cells’ plasma membrane lies at the heart of many crucial cellular processes. Traditionally, it has been thought to function through interactions among its various proteins and lipids. Now, researchers have revealed a crucial yet often overlooked membrane component – complex sugar chains, known as glycans, carried by certain membrane lipids called gangliosides and many membrane proteins.

Published in Nature Communications, a team from the Okinawa Institute of Science and Technology (OIST), Gifu University, the National Cancer Center Research Institute in Japan, Kyoto University and collaborators show that glycans on gangliosides in the same plasma membrane form weak, short-lived pairs. Repeated “fleeting encounters” of the glycans help couple the gangliosides, build membrane nanodomains and regulate epidermal growth factor receptor (EGFR) signaling, which in turn modulates cell division. 

Whether glycan-glycan interactions occur between molecules in the same plasma membrane has long challenged biologists. Using our advanced single-molecule imaging techniques, we were able to see these extremely weak, short-lived, but frequent interactions directly in living cell membranes.” 

Professor Akihiro Kusumi, head of OIST’s Membrane Cooperativity Unit and study author

The researchers chemically synthesized 39 fluorescent ganglioside analogs of all major ganglioside families distinguished by their glycan chains, and introduced them into artificial and living cell membranes. Single molecules were tracked individually, which revealed that gangliosides from all major families repeatedly formed short-lived “homodimers”, in which two identical ganglioside molecules paired with each other via glycan-glycan interactions. These homodimers lasted only about 0.1 to 0.2 seconds before falling apart, but new pairs were constantly forming. 

“Our cell membranes are bustling environments, with molecules constantly moving, meeting and separating,” says Kusumi. “Sugar chains do not need to form stable complexes. Instead, they meet only for a fraction of a second, but they do so again and again.”

Fleeting pairs, lasting control 

Across a lifetime, our cells divide around 10 quadrillion times. Knowing when to divide, and when not to, is key to healthy tissue development. Excessive cell division is a distinctive feature of cancers. 

Sitting within our cell membranes, epidermal growth factor receptor (EGFR) glycoproteins, which carry glycan chains, play central roles in regulating cell division and are often involved in cancer development. When EGFR molecules couple together to form dimers, signals are sparked within the cell that can initiate cell division. Usually, this coupling is triggered by binding of a molecule called EGF, but these dimers can also form incidentally, without EGF binding. Abnormal EGFR activation is known to occur in cancer. 

One key finding involved GM3, a ganglioside known to influence EGFR. The study showed that GM3 suppresses EGFR dimerization only when GM3 forms homodimers. The two coupled glycans of the GM3 dimer bind to two EGFR glycans. Although these binding events are transient, many repeated brief contacts allow GM3 homodimers to act as a constantly renewed brake on EGFR, reducing unwanted EGFR dimerization in the absence of extracellular stimulation.

“These GM3-EGFR glycan interactions represent a new type of control mechanism for growth-receptor signaling,” says Kusumi. “Cells appear to keep EGFR in check not through a long-lasting molecular clock, but through many repeated, momentary contacts.” 

The researchers also found that ganglioside homodimers cooperate with cholesterol to form rafts, nanometer-scale, ordered-liquid clusters in the plasma membrane. These rafts repeatedly appear and disappear while transiently recruiting other molecules. These results suggest that temporary ganglioside pairs serve as basic building units for dynamic membrane nanostructures: tiny nanorafts are constantly born, disappear and reassemble, helping organize the plasma membrane over time. 

The findings point to a new principle of membrane regulation: extremely short molecular interactions, when repeated many times, can generate stable effects over much longer timescales. By revealing how fleeting sugar pairings help regulate EGFR and membrane nanodomains, the study may inspire future strategies to modulate receptor signaling by targeting glycan-glycan interactions or the glycan environment around membrane receptors. This new concept may also provide new inspiration for cancer biologists seeking to inhibit tumor cell replication.