A team of biochemists at the University of Pennsylvania has successfully "reprogrammed" the sugar molecule-based communication ports that blanket the outside of cell membranes. It's a notable first, not just for the technique's enormous potential in diagnosing and treating human disease, but for offering a new and rare insight into a biological process that's largely evaded observation—a powerful tool for understand the hows and whys of cell-by-cell behavior and interactions.
In question are complex carbohydrates called glycans which, as explained in a paper published this week in the Proceedings of the National Academy of Sciences, act as "docking sites" on the surface of a cell. When some cell-to-cell or cell-to-matrix (matrix: the gunk in between cells) signaling protein comes floating around, it may bind to a glycan molecule, which passes some message onward into the cell via chemical reaction.
Glycans attach to a particular category of cell signaling protein known as galectins. These molecules are hugely important in the development of many if not most human diseases, including cancer, HIV, autoimmune disease, chronic inflammation, graft vs host disease, and everday allergic reactions. Basically, these are the diseases of the human body going haywire—turning on itself, really.
The glycan part of cell membranes had been something of a mystery until last year when the same Penn team first came up with a way of modeling them by creating artificial and, yes, programmable membranes featuring a customizable array of surface sugar molecules. The new work adds an IRL demonstration to the research, actually binding galectins to the artificial membrane.
The Penn researchers' programmable membrane is more of a means to an end than an end in itself. And that end is an better understanding of how cellular communication fucks up. This is a fuzzy area.
"The sociology of cells critically depends on selective interactions between cells and the extracellular matrix," the current paper notes. "Taking advantage of the capacity of carbohydrates to store biological information, glycans are a versatile means to generate the required cell-surface recognition."
The researchers tested their programmable model by observing its interactions with galectin-8 (gal-8), a signaling protein whose mutation is implicated in the development of rheumatoid arthritis, a common and brutal chronic inflammation of the joints. By tweaking a single component in gal-8's structure, the team was able to limit its ability to communicate with the artificial membrane. The suggestion is that this common autoimmune illness—which has no cure—may have a molecular origin.
"By testing this model with a sugar binding protein of human origin, we show that single mutation of an amino acid from a giant protein structure can induce a dramatic change in its interactions with the cell," Virgil Percec, a Penn chemistry processor and lead author of the new paper, offers. "This demonstrates just how efficient and sensitive a model this is for biological membranes."